CN1088213A - Contain the quaternary nitrogen phosphinic acid compounds, pharmaceutical composition and treatment calcium and the unusual method of phosphate metabolism and treatment prevention tartar and dental plaque method - Google Patents

Contain the quaternary nitrogen phosphinic acid compounds, pharmaceutical composition and treatment calcium and the unusual method of phosphate metabolism and treatment prevention tartar and dental plaque method Download PDF

Info

Publication number
CN1088213A
CN1088213A CN93108278A CN93108278A CN1088213A CN 1088213 A CN1088213 A CN 1088213A CN 93108278 A CN93108278 A CN 93108278A CN 93108278 A CN93108278 A CN 93108278A CN 1088213 A CN1088213 A CN 1088213A
Authority
CN
China
Prior art keywords
group
alkyl
unsubstituted
compound
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN93108278A
Other languages
Chinese (zh)
Other versions
CN1042031C (en
Inventor
F·H·艾贝丁诺
S·M·卡斯
M·D·弗朗西斯
D·G·纳尔逊
J·M·曾努茨
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Chilcott Pharmaceuticals Inc
Original Assignee
Procter and Gamble Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/052,695 external-priority patent/US5391743A/en
Application filed by Procter and Gamble Pharmaceuticals Inc filed Critical Procter and Gamble Pharmaceuticals Inc
Publication of CN1088213A publication Critical patent/CN1088213A/en
Application granted granted Critical
Publication of CN1042031C publication Critical patent/CN1042031C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/5765—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)

Abstract

The present invention relates to contain quaternary nitrogen phosphonic acids and medicinal salt and ester thereof, and have structure as general formula.
The invention still further relates to the The compounds of this invention that contains a kind of safety and significant quantity and the pharmaceutical composition of pharmaceutical excipient.At last, the invention still further relates to treatment or preventing with abnormal calcium and phosphate metabolism is the method for the pathological state of feature, as treat the method for osteoporosis, rheumatoid arthritis and osteoarthritis in human body or other mammalian bodies, and relate to the method for the treatment of or preventing tartar, dental plaque and gingivitis.This method comprises The compounds of this invention or the composition that uses safety and significant quantity to the human body of this treatment of needs or other Mammalss.

Description

Contain the quaternary nitrogen phosphinic acid compounds, pharmaceutical composition and treatment calcium and the unusual method of phosphate metabolism and treatment prevention tartar and dental plaque method
The present invention relates to the new phosphonate that contains quaternary nitrogen (ester) compound; comprise diphosphonate (ester); phosphine acyl-alkyl phosphinates (ester); phosphono-carboxylic acids salt (ester); with phosphono sulfonate (ester); preferred diphosphonate (ester); with phosphine acyl-alkyl phosphinates (ester); the invention still further relates to the pharmaceutical composition that contains these new compounds and use a kind of compound of the present invention or medicine composite for curing or prevent some to be the method for the metabolic osteopathy of feature unusually with calcium and phosphate metabolism; specifically; the present invention relates to the method for a kind of use The compounds of this invention or medicine composite for curing or preventing osteoporosis and sacroiliitis, especially rheumatoid arthritis and osteoarthritis.The invention still further relates to pharmaceutical composition and treatment that contains these new compounds or the method for preventing tartar, dental plaque and gingivitis.Specifically, the invention still further relates to the method for a kind of compound of a kind of the application of the invention or medicine composite for curing or prevention tartar, dental plaque.
The metabolic disturbance of phosphoric acid salt and calcium
Some pathological conditions that influence warm-blooded animal relate to calcium and phosphate metabolism is unusual.These situations can be divided into two big classes.
1. the feature of a class pathological condition is because calcium and phosphatic metabolic disturbance cause general or partial bone loss, as osteoporosis and Paget's disease (Paget ' s disease), or calcium and phosphatic too high levels in the body fluid, as come from the hypercalcemia of tumour.This pathological condition this paper is referred to as pathologic sclerous tissues demineralize (effect) sometimes.
2. another kind of pathological condition can cause or result from calcium and phosphatic abnormal deposition in the body, as sacroiliitis, comprises rheumatoid arthritis and osteoarthritis.This pathological condition is referred to as pathologic calcification sometimes at this paper.
The first kind comprises prevailing metabolic osteopathy, osteoporosis; Osteoporosis is the pathological condition that a kind of bone hard tissues disproportional loss produces new sclerous tissues.Osteoporosis generally may be defined as the minimizing of bone mass or the atrophy of bone tissue.Matter increases between marrow and bone, and fibrous connective tissue reduces, and fine and close bone becomes fragile.Osteoporosis can also be further divided into the menopause osteoporosis, senile osteoporosis, drug-induced osteoporosis (as, adrenocortical steroid causes, can use in steroid therapy); (sacroiliitis and tumour) osteoporosis that disease causes, etc.; But, its performance is consistent basically.Two types osteoporosis is arranged in general: primary osteoporosis and secondary osteoporosis." secondary osteoporosis " is to be caused by a kind of other legible lysis or medicament.But about 90% is " primary osteoporosis " in all osteoporosis cases.This primary osteoporosis comprises postmenopausal osteoporosis, disuse osteoporosis, age related osteoporosis (can influence the age most of people of 70 to 80 years old) and influence middle age and young man's idiopathic osteoporosis.
For some osteoporosis sick body, the extent of damage of osseous tissue is very serious so that can cause the mechanicalness fracture of bone structure.For example, hip and spinal fracture often appear in the women who suffers from postmenopausal osteoporosis.Can also cause hunchback (the unusual overbending of chest backbone).
The mechanism of bone loss is considered to relevant with the imbalance in " bone reconstruction " process in the osteoporosis.Bone all taking place in whole vital process rebuild, upgrade bone, keeps the strength of calligraphic strokes.This process of reconstruction comprises the loss of bone surface evacuation part and replenishes that this process is finished by one group of cell tissue group who is referred to as " basic many cells unit " or " BMUs ".BMUs mainly is made up of " osteoclast ", " scleroblast " and cell precursors thereof.In rebuilding working cycle, osseous tissue is absorbed by osteoclast in " activatory " BMU site, forms one and absorbs air-conditioning.This cavity and then fill osseous tissue by scleroblast.
Under the normal circumstances, adult reconstruction circulation not exclusively can cause the damaged on a small quantity of bone owing to absorb the filling in cavity.Therefore, even in the middle of health adult, the loss of age related bone can take place also.But, in the osteoporosis case, activatory BMUs quantity can increase.This activatory increases and can accelerated bone rebuild, and causes that unusual bone loss is too high.
Although its nosetiology is unclear fully as yet, there are a lot of Hazard Factor to be considered to relevant with osteoporosis, these factors comprise under-weight, and low calcium is taken in, and physical exertion is few, and estrogen deficiency.
At present osteoporotic treatment mainly is to use calcium agent and oestrogenic hormon.
The pathological condition that second class relates to shows as unusual calcium and phosphatoptosis, comprise progressive ossifying myositis, calcinosis universalis, with more following illnesss such as sacroiliitis (comprise, for example, rheumatoid arthritis and osteoarthritis), neuritis, bursitis, tendonitis and make related tissue the more sedimentary pathological conditions of calcium occur.
Except osteoporosis, rheumatoid arthritis and osteoarthritis also can cause the bone loss.Scorching rheumatic arthritis is a kind of chronic, systematicness and joint property inflammatory diseases, it is characterized in that the unable of joint capsule and ligament, follows by cartilage.The damage of ligament, tendon and bone, and the viscosity of synovia reduces and other changes.Symptoms of rheumatoid arthritis comprises that general is unable, and is tired, stiff, unable, the swelling in local pain, body joint and deformity.Rheumatoid arthritis is the most common to the sexagenarian women 40.
Cause the pathogeny of the rheumatoid arthritis of joint injury, be characterized as and be divided into two stages:
1) ooze out the phase, this stage has influence on microcirculation and myxocyte, makes plasma proteins and cell composition flow into the joint, with 2) the chronic inflammatory phase, betide under the synovial membrane and under the cartilage, it is characterized in that in joint cavity, forming pannus (granulation tissue), bone loss and cartilage injury.This pannus can form viscosity and scar tissue.The joint deformity feature that causes rheumatoid arthritis.
The nosetiology of rheumatoid arthritis remains unclear.Infectious factors such as bacterium, viral relevant with it.Present hypothesis thinks that Epstein-Barr virus (Epstein-Barr Virus) is a kind of paathogenic factor of rheumatoid arthritis (EBV).
The methods of treatment of rheumatoid arthritis mainly is by using nonsteroidal antiinflammatory drug to come relief of symptoms at present.The nonsteroidal antiinflammatory drug therapy mainly is effective to early stage rheumatoid arthritis; If the course of disease surpasses 1 year, then can not produce restraining effect to arthritis.Once attempted with golden preparation, methotrexate, immunosuppressor and corticosteroid treatment and produced limited disease to imitate.
On the other hand, osteoarthritis is the non-inflammatory disease of a kind of movable joint inside, it is characterized in that the degeneration and the wearing and tearing of joint cartilage, and forms new bone at articular surface.Along with the development of osteoarthritis, articular cartilage surface is damaged, and wear particle enters synovia, and synovia excites engulfing of scavenger cell conversely.Therefore, finally bring out bone and close Inflammatory response in the inflammation.The general clinical symptom of osteoarthritis comprises the cartilage of articulations digitorum manus and bone increase and WA ankylosis, motion pain.
General symptom treatment for osteoarthritis comprises use anodyne, antiphlogiston, steroid and physiatrics.
Tartar and dental plaque
Dental plaque is a kind of coarse adhesive film of being made up of saliva, bacterium and food particles, and it is irregular or dispersed spot securely attached on the tooth.Dental plaque can cause gum point and tooth degeneration, if let alone to accumulate the basis that can become tartar, also is called dental calculus (tartar), a kind of hard calcified deposits.
If derive from the mineral salt in the saliva, mainly be phosphorus and calcium, be wrapped in the dental plaque, form the hard-caked sediment shell, just formed tartar.Tartar tends to forming near the saliva tube opening: the lingual surface of lower front tooth and on grind one's teeth in sleep far away in surface formation.
In case form sophisticated tartar, unless use some external reagent dyeing or decolouring, tartar can be changed into visible white or yellow.Except not the needing of not attractive in appearance and aesthetic aspect, tartar still continues to be covered by dental plaque.Toxin in dental plaque and the tartar stimulates gum, causes the scorching disease and the atrophy of gum, causes other complication.
Once suggestion is in the prior art used various chemistry and biotechnological formulation to delay the formation of tartar or remove tartar after tartar is formed.The chemical process of restriction tartar generally comprises the method for the inhibition crystallization generation that prevents that tartar from forming.The calcium ion chelating can destroy sophisticated tartar by removing calcium, but since it also can remove normal calcified tissue and not be accepted.Certainly these material demands of odontologist's machinery removal regularly regularly go dental clinic to finish.
Once suggestion uses various phosphonate derivatives to treat and prevention and abnormal calcium, phosphorus metabolism diseases associated.For example, some reference that this paper quoted disclose the composition that contains polyphosphonic acid, especially di 2 ethylhexyl phosphonic acid, as ethane-1-hydroxyl-1,1-di 2 ethylhexyl phosphonic acid (" EHDP ") and they are the application aspect calcium and phosphoric acid salt abnormal deposition and the metabolism in suppressing animal tissues: the United States Patent (USP) 3 of Francis, 683,080, be disclosed on August 8th, 1972, with United States Patent (USP) 4,230,700, be disclosed in the United States Patent (USP) 4 of on October 28th, 1980 and September in 1989 disclosed Ebetino on the 19th, 868,164.The phosphonic acids that some other reference have been described heterocyclic substituted can be used for treating sclerotin pine and/or sacroiliitis, and this paper combines these reference: December in 1991 disclosed Ebetino on the 10th United States Patent (USP) 5,071,840; September in 1989 people such as disclosed Ebetiuo on the 19th application patent 4,868,164; April in 1992 people such as disclosed Benedict on the 14th United States Patent (USP) 12, people's such as disclosed Blum in 5,104,863,1981 on May United States Patent (USP) 4,267,108; May in 1988 people such as disclosed Breliere on the 24th United States Patent (USP) 4,746,654; April in 1989 people such as disclosed Barbier on the 24th United States Patent (USP) 4,876,247 and on February 15th, 1984 disclosed Breliere Europe patent application publication number No.100,718; On February 5th, 1986 disclosed Boehringer Mannheim GmbH Europe patent application publication number 170,228; On July 2nd, 1986 disclosed Benedict and Perkins Europe patent application publication number No.186,405; On January 11st, 1989 disclosed Ebetino Europe patent application publication number No.298,553; Be disclosed in the people's such as Bosies on November 15th, 1988 United States Patent (USP) 4,754,993; Nineteen ninety 7 is people's such as disclosed Jaeggi on the 3rd United States Patent (USP) 4,939,130 month in and month out; November nineteen ninety people such as disclosed Bosies on the 20th United States Patent (USP) 4,971,958; October nineteen ninety people such as disclosed Dunn on the 18th Wo 90/12017; On July 25th, 1991 disclosed Youssefyeh, R. waits people's WO 91/10646; June in 1989 disclosed Jaeggi on the 15th patent AU-A-26738/88; May nineteen ninety disclosed Ciba-Geigy on the 31st patent AU-A-45467/89.
At last, June in 1980 disclosed Bauman on the 17th United States Patent (USP) 4,208,401 non-heterocyclic substituted disclosed the quaternary ammonium diphosphonate as anticalculus agent.
October 18 nineteen ninety disclosed Jaeggi, K., DE 40 11 777(DE'777) a kind of diphosphonate of heterocyclic substituted is disclosed, wherein said heterocycle can be replaced by low alkyl group.Said heterocycle is by a kind of acyclic quaternary nitrogen atoms and phosphonyl group bridging.DE'777 also discloses this compound can suppress bone resorption significantly, thereby is used for the treatment of osteoporosis, inflammatory and degenerative arthropathy, periodontopathy, hyperparathyroidism.The present invention is with reference to having quoted the specification sheets of these patents and application.
But there be not to describe the purposes of heterocycle phosphonate (ester) compound in prevention and treatment osteoporosis, sacroiliitis or prevention tartar, dental plaque and gingivitis that contains a kind of quaternary nitrogen in these reference.
It is active that the joint injury position of The compounds of this invention in sacroiliitis pathology situation has the bone protection, and this activity is alleviated inflammatory symptoms than above-mentioned and had extra benefit aspect treatment of arthritis.Term used herein " the bone protection is active " is meant the disease-repairing activity to bone and surrounding soft tissue at the joint injury position.
Be surprised to find the heterocycle phosphonate compound that contains a quaternary nitrogen atoms of the present invention, have stronger fracture assimilating activity and the therepic use in treatment preventing osteoporosis, sacroiliitis (comprising rheumatoid arthritis and osteoarthritis) and tartar and dental plaque than the heterocyclic phosphonate compound that contains that does not contain quaternary nitrogen atoms.And compound of the present invention shows unusual solubility.Therefore, The compounds of this invention can be easier to by oral absorption.A kind of compound is easy more to be absorbed, just effective more when low dosage.General preferred than low dosage, because can reduce the unnecessary effect of paying like this.
Therefore, a goal of the invention of the present invention provides new more effective compound, is used for the treatment of osteoporosis and as anti-arthritic (in particular for treatment osteoarthritis and scorching rheumatic arthritis) and be used for the treatment of and prevent tartar and dental plaque.Another goal of the invention of the present invention provides pharmaceutical composition and is used for the treatment of and preventing osteoporosis and sacroiliitis, especially rheumatoid arthritis and osteoarthritis.In addition, an object of the present invention is to provide the method for the treatment of or preventing osteoporosis, rheumatoid arthritis and osteoarthritis.Another object of the present invention provides treatment or prevents the method for tartar and dental plaque.
Detailed description by following specification sheets of the present invention can make these and other purpose of the present invention more obvious.
The present invention relates to contain the heterocycle phosphinic acid compounds of quaternary nitrogen, and pharmaceutically acceptable salt or ester, have following general formula:
Wherein m and n are 0 to 10 integers; M+n is from 0 to 10;
(a) Q is that a covalent linkage or one are selected from O, S, NR 1Group;
(b) Y is N +(R 8) 2Or C(R 1) 2With working as Y is C(R 1) 2The time, at least one R 2Must be N +(R 8) 3;
(C) Z be one saturated, undersaturated, or aromatic, monocycle or encircle carbocyclic ring more or contain one or several and be selected from O, the heteroatomic heterocycle of S or N,
(d) R is COOH; PO 3H 2; SO 3H; Or P(O) (OH) R 4, R wherein 4Be 1-8 carbon atom replacement or unsubstituted alkyl;
(e) each R 1Be in following one group, to select: zero; SR 6; R 9SR 6; Hydrogen; Hydroxyl; Replace or unsubstituted C 1-C 8Alkyl;-OR 3;-CO 2R 3;-NR 32;-N(R 3) C(O) R 3;-C(O) N(R 3) 2; Halogen;-C(O) R 3; Arylalkyl; Nitro; Replace or unsubstituted aryl and their combination;
(f) each R 2Be the one or more substituting groups on the Z group, they are independently selected from following one group of group: N +(R 8) 3; SR 8; R 9SR 6; Hydrogen; That replace or unsubstituted C 1-C 8Alkyl; OR 3;-CO 2R
Figure 931082781_IMG5
;-O 2CR 3;-NR 32;-N(R 3) C(O) R 3;-C(O) N(R 3) 2; Halogen; Hydroxyl;-C(O) R 3; Arylalkyl; Nitro; Replace or unsubstituted aryl;
(g) each R 3Be to be independently selected from following one group of group: hydrogen, have the replacement or the unsubstituted alkyl of 1-8 carbon atom, and R 9SR 6;
(h) R 5Be selected from following one group of group: hydrogen; Halogen; SR 6; R 9SR 6; Amino; Hydroxyl; With replacement or unsubstituted C 1-C 8Alkyl;
(i) each R 6Be independently selected from following one group of group: H;-C(O) R 7;-C(S) R 7;-C(O) NR 72;-C(S) N(R 7) 2;-C(S) OR 7;-C(O) OR 7; R wherein 7Be hydrogen or replacement or unsubstituted C 1-C 8Alkyl.
(j) each R 8Be independently selected from following one group of group: zero, replace or unsubstituted alkyl with 1-35 carbon atom, replace or unsubstituted phenyl benzyl, or R 9SR 6; With
(k) R 9Be a replacement or unsubstituted C 1-C 8Alkyl;
In this general formula, Z is a monocycle or polycyclic, saturated or undersaturated heterocyclic group, and also Y is N +(R 8) 2Or C(R 1) 2In addition, m and n and m+n are from 0 to 10 integers, and Q is that a covalent linkage or one are selected from oxygen, sulphur or NR 1Group in one group of composition.And in this general formula, each R 1Be to be independently selected from various substituting group, most preferably R 9SR 6And hydrogen, each R 2Be a substituting group on the heterocycle, be selected from various substituting group, preferred N +C(R 8) 3, C 1-C 8Alkyl, amino, hydroxyl, halogenide, alkoxyl group or R 9SR 6, when Y be C(R 1) 2The time, at least one R 2Must be N +(R 8) 3Each R is independently selected from following one group of group: COOH, SO 3H, PO 3H 2, and P(O) (OH) R 4, R wherein 4It is a low alkyl group.R 5Be selected from various substituting groups, most preferably hydrogen, hydroxyl, halogen and amino.R 6Be to be selected from various substituting groups, most preferably H and-C(O) R 7With-C(S) R 7, R wherein 7Be that replace or unsubstituted C 1-C 8Alkyl.R 8Be to be selected from replacement or unsubstituted C 1-C 35Alkyl, preferred C 1-C 8; That replace or unsubstituted phenyl; Benzyl; Or R 9SR 6R 9Be that replace or unsubstituted C 1-C 8Alkyl, preferred C 1-C 4Alkyl.
The invention still further relates to the The compounds of this invention that contains a kind of safety and significant quantity and the pharmaceutical composition of pharmaceutical carrier.At last, the invention still further relates to treatment or preventing with calcium and phosphate metabolism is the method for the pathological condition of feature unusually, these pathological conditions comprise as osteoporosis, rheumatoid arthritis and osteoarthritis in human body or other Mammalss, also relate to the method for the treatment of or preventing tartar, dental plaque and gingivitis.This method comprises The compounds of this invention or the composition that uses safety and significant quantity to the human body of this treatment of needs or other Mammalss.
Be the definition of a series of terms used herein below.
" heteroatoms " is nitrogen, sulphur, or Sauerstoffatom.Contain one or more heteroatomic groups and can contain different heteroatomss.
" alkyl " is a kind of unsubstituted or replace, straight or branched, the hydrocarbon chain of saturated or insatiable hunger, said hydrocarbon chain can be the saturated chain with 1 to 8 carbon atom, and unless otherwise indicated, preferred 1 to 4 carbon atom; Said hydrocarbon chain can be the unsaturated chain with 2 to 8 carbon atoms, and unless otherwise indicated, preferred 2 to 4 carbon atoms.Therefore, this term used herein " alkyl " comprises the alkenyl hydrocarbon unsaturated chain with the two keys of at least one alkene and has at least one triple-linked alkynyl hydrocarbon unsaturated chain.Preferred alkyl includes, but are not limited to, methyl, ethyl, propyl group, sec.-propyl and butyl.
" carbocyclic ring " used herein is a unsubstituted or replacement, saturated, unsaturated or fragrant hydrocarbon ring.Carbocyclic ring can be monocycle or many rings; Monocycle generally contains 3 to 8 each and every one atoms, preferred 5 to 7 atoms; The many rings that contain two rings contain 6 to 16, preferred 10 to 12 atoms; And those many rings that have three rings generally contain 13 to 17, preferred 14 to 15 atoms.
" assorted alkyl " is a kind ofly to have 3 to 8 yuan unsubstituted or replace, saturated chain, and contain carbon atom and one or two heteroatoms.
" heterocycle " used herein is a kind of unsubstituted or replacement, and saturated, unsaturated or fragrant ring contains carbon atom and one or several heteroatoms in this ring.Heterocycle can be monocycle or many rings.Monocycle generally contains 3 to 8 atoms, preferred 5 to 7 atoms.Contain two general multi-loop systems of ring and contain 6 to 16, preferred 10 to 12 atoms.The multi-loop system that contains three rings generally contains 13 to 17 atoms, preferred 14 to 15 atoms.Heterocyclic group can be made up of heterocycle or heterocycle and carbocyclic ring.Each heterocyclic radical must have at least one nitrogen-atoms.Unless otherwise indicated, any extra heteroatoms can be to be independently selected from nitrogen, sulphur, and oxygen.
" aryl " is an aromatic carbocyclic.Preferred aryl groups includes, but are not limited to, phenyl, tolyl, xylyl, cumenyl, and naphthyl.
" heteroaryl " is an aromatic heterocycle.Preferred heteroaryl includes, but are not limited to thienyl, furyl, pyrryl, pyridyl, pyrazinyl ， oxazolyl, thiazolyl, quinolyl, pyrimidyl, and tetrazyl.
" alkoxyl group " be one and have the substituent Sauerstoffatom of hydrocarbon chain, wherein hydrocarbon chain be an alkyl or alkenyl (as ,-O-alkyl or-the O-alkenyl).Preferred alkoxyl group includes, but are not limited to methoxyl group, oxyethyl group, propoxy-, and alkoxyl group.
" hydroxyalkyl " is monobasic hydrocarbon chain, it have a hydroxyl substituent (as ,-OH), and can have other substituting group.Preferred hydroxyalkyl includes, but are not limited to hydroxyethyl and hydroxypropyl.
" carboxyalkyl " is a replacement hydrocarbon chain with carboxyl substituent (as COOH), and can have other substituting group.Preferred carboxyalkyl comprises carboxymethyl, propyloic, and acid and ester.
" aminoalkyl group " by an amino (as, NH-alkyl-) a kind of hydrocarbon chain (as alkyl) of replacing as aminomethyl.
" alkylamino " is that a kind of amino with one or two alkyl substituent (as-N-alkyl) is as dimethylamino.
" alkenyl amino " is a kind of amino with one or two alkenyl substitutents (as-N-alkenyl).
" alkynyl amino " is a kind of amino with one or two alkynyl substituted base (as ,-N-alkynyl)
" alkyl imino " be a kind of imino-with one or two alkyl substituent (as-N-alkyl-).
" arylalkyl " is a kind of alkyl that is replaced by aryl, and the preferred aryl groups alkyl comprises benzyl and phenylethyl.
" arylamino " is a kind of amino that is replaced by aryl (as-NH-aryl).
" aryloxy " is a kind of Sauerstoffatom with an aryl substituent (as ,-O-aryl).
" acyl group " or " carbonyl " is meant two keys that carbon is connected with Sauerstoffatom, as, R-C(=0).Preferred acyl group includes, but are not limited to ethanoyl, propionyl, butyryl radicals, and benzoyl.
" acyloxy " is meant Sauerstoffatom with an acyl substituent (as ,-O-acyl group); For example ,-O-C(=0)-alkyl.
" acyl amino " is meant a kind of amino with acyl substituent (as ,-N-acyl group); For example ,-NH-(C=0)-alkyl.
" halogen " or " halogenide " is meant chlorine, bromine, fluorine or iodine atomic radical.Chlorine, bromine and fluorine are preferred halogens.
As described herein, one " rudimentary " hydrocarbyl group (as " rudimentary " alkyl) is meant unless otherwise indicated by 1 to 6, the hydrocarbon chain that preferred 1 to 4 carbon atom is formed.
And, as described herein, this term " sulphur substituting group "-(SR 6Or R 9SR 6) comprise wherein R of sulfydryl [SH] 6=H; Thioesters [SC(O) R 7] R wherein 6=C(O) R 7; Dithioesters [SC(S) R 7] R wherein 6=C(S) R 7; Thiocarbamate [SC(O) N(R 7) 2] R wherein 6=C(O) N(R 7) 2; Dithiocarbamate [SC(S) N(R 7) 2] R wherein 6=C(S) N(R 7) 2; Thiocarbonic ester [=SC(O) OR 7] R wherein 6=C(O) OR 7; And dithiocarbonates [SC(S) OR 7] R wherein 6=C(S) OR 7R 7Be hydrogen or replacement or unsubstituted C 1-C 8Alkyl.Any SR 6Substituting group itself can be by a R 9Group replaces, wherein R 9Being one replaces or unsubstituted C 1-C 8Alkyl.Therefore, with R 9SR 6Other sulphur substituting group of expression is an alkyl thiol, alkylthio ester, dithio alkyl ester, thiocarbamate alkyl ester, dithiocarbamic acid alkyl ester, thiocarbonic acid SOH alkyl ester and dithiocarbonic acid alkyl ester.
Term used herein " bisphosphonate " or " two phosphonic acids " are meant those phosphonic acid esters or the phosphonic acids that is linked with two phosphonate groups on same carbon atom, and can exchange use with term " bisphosphonates " and " di 2 ethylhexyl phosphonic acid ".Use structure described herein, the R group is PO 3H 2
A kind of " medicinal " salt is meant cationic salts that forms or the anion salt of going up formation at any base groups (as amino) on any acid (as carboxyl) group.Many this salt are as known in the art, disclose as described in 87/05297 as the people's such as Johnston that published at 1987 11 days on the 9th world patent, are combined in herein by reference this article.Preferred cation salt comprises an alkali metal salt (as sodium and potassium) and alkaline earth salt (as magnesium and calcium).Preferred anionic surfactants salt comprises halogenide (as muriate), acetate and phosphoric acid salt.
A kind of " but ester of biological hydrolysis " is meant a kind of ester that contains the heterocycle phosphinic acid compounds of quaternary nitrogen, and it does not influence the therapeutic activity of this compound, or easily by people or the moving metabolism of other lactations.Many this esters are well known in the art.As at world's patent disclosure specification sheets 87/05297, (publication on September 11st, 1987) is combined in herein by reference this article described in the Johnston et al..These esters comprise lower alkyl esters, the low-grade acyloxy alkyl ester is (as the acetoxy-methyl ester, the acetoxyl group ethyl ester, aminocarboxyl oxygen base methyl esters, the new pentane acyloxy methyl esters, with the new pentane acyloxy ethyl ester), lactone group ester (as phthalidyl ester and sulfo-2-benzo [2] furanonyl ester), lower alkoxy acyloxy alkyl ester is (as methoxycarbonyl oxygen base methyl esters, oxyethyl group carbonyl oxygen base ethyl ester and isopropoxy carbonyl oxygen base ethyl ester) alkoxy alkyl, cholinesterase and amidoalkyl ester (as the kharophen methyl esters).
Employed as above-mentioned definition and this paper, substituted radical itself can be substituted.This replacement can be by one or more substituting groups.These substituting groups comprise, but be not limited to, list in the Substituent Constants for Correlation Analysis in Chemistry and Biology(1979 that C.Hansch and A.Leo show) those substituting groups in the book, combine this book by reference this paper.Preferred substituted includes, but not limited to alkyl, alkenyl, alkoxyl group, hydroxyl; the oxygen base, amino, oxygen base alkyl (as amino methyl, etc.), cyano group; halogen, carboxyl, the alcoxyl ethanoyl (as the carbonyl oxyethyl group, etc.), sulfo-; sulfydryl, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl is (as piperidyl; morpholinyl, piperazinyl, pyrrolidyl, etc.), imido grpup; sulfo-, hydroxyalkyl, aryl oxide, arylalkyl, and their combination.
The heterocycle phosphinic acid compounds that contains quaternary nitrogen
The compounds of this invention is to contain the quaternary nitrogen phosphinic acid compounds, and pharmaceutical salts and ester, and wherein the phosphonic acids of carbon atoms is connected at a monocycle or encircles on the carbon atom in the heterocyclic group more.Binding from the phosphonic acids of carbon atoms to heterocyclic group can be directly by covalent linkage (preferred singly-bound), or links by the chain of 1 to 10 carbon atom of length.If this binding is by a coupling chain, this chain can be whole carbon atoms, a nitrogen-atoms or nitrogenous chain, a Sauerstoffatom or contain the oxygen chain, or sulphur atom or sulfur-bearing chain.Carbon atom in this coupling chain and nitrogen-atoms can be unsubstituted independently or be selected from methyl, ethyl, propyl group, SR 6And R 9SR 6In one or more substituting group replace.Unsubstituted carbon atom in this chain and nitrogen-atoms are preferred.But also the chain of a preferred atomic length, that is, and-CH 2-,-NH-,-S-and-O-.
For the sulphur in this coupling chain, nitrogen or Sauerstoffatom and heterocyclic group banded compound, this sulphur, nitrogen or Sauerstoffatom are continuously to the carbon atom of ring rather than directly be attached on the nitrogen-atoms of ring.Be attached to compound on the heterocycle for the carbon in this continuous chain, this carbon can be continuously to the carbon atom of ring or directly be attached on the nitrogen-atoms of ring.
The carbon atom that is connected with phosphonyl group can be unsubstituted (that is, a hydrogen atom), or replace.This phosphonic acids carbon can contain two phosphonyl groups, forms a diphosphine compound; A phosphonyl group and a carboxylate group form a phosphonocarboxylic acid salt (ester) compound; Phosphonyl group and a sulfonate (ester) group, form a phosphonic acids sulfonate (ester) compound, phosphinates (ester) group and a phosphonyl group, form a phosphonic acids alkyl phosphinate (ester), and the carbon atom in the heterocycle can be unsubstituted or be replaced by one or multi-substituent independently.Nitrogen-atoms on the heterocycle can be (Y=N +(R 8) 2) or be not (Y=C(R 1) 2) quaternary, but containing the heterocyclic phosphinic acid compounds must be at least one Y or R 2Contain a quaternary nitrogen atoms in the substituting group.Therefore, perhaps Y=N +(R 8) 2Or at least one R 2=N +(R 3) 3
Therefore, the present invention contains the saturated of quaternary nitrogen and unsaturated heterocycle phosphinic acid compounds and pharmacy acceptable salt and ester, has general formula:
Figure 931082781_IMG6
In this general formula, Z be one nitrogenous season ring filling, undersaturated or aromatic, monocycle or encircle isocyclic or heterocyclic group more.Said heterocyclic group contains one or more other heteroatomss that are selected from oxygen, sulphur or nitrogen.
Z group of the present invention can be a heterocyclic group; Said heterocyclic group can have the O of being selected from, one or more heteroatomss of S or N; At least one is a quaternary nitrogen.This Z group can be monocyclic heterocycles or the carbon ring group with 3-8 atom, or it can be many rings heterocycle or the carbon ring group with 7-17 atom.Said many cyclic groups can contain two or more heterocycles, two or more carbocyclic rings, a carbocyclic ring and one or more heterocycle, or a heterocycle and one or more carbocyclic ring.Preferred Z heterocyclic group contains at least one quaternary nitrogen atoms and preferred monocycle Z group is: pyrimidine (Pyrimidinium), basic pyridine, pyridine, quinoline, pyrrolopyridine, quinoxaline, imidazopyridine (inidazopyridinium).
In this general formula, Y is a member in the Z cyclic group, and can be N +(R 8) 2Or C(R 1) 2Q be a covalency chain (preferred strand) or be selected from oxygen ,-NR 1-or sulphur in a group.And m and n and m+n are 0 to 10 integers, preferred m+n=0 or 1.Q can be a covalent linkage, oxygen, and sulphur, or-NR 1; Preferred Q is a covalent linkage; M+n=0,1,2 or 3.R group described herein can be COOH; SO 3H; PO 3H 2Or P(O) (OH) R 4, R wherein 4Be C 1-C 8Alkyl; Preferred R is PO 3H 2Or P(O) (OH) R 4
R 1Group is selected from zero, SR 6, R 9SR 6Hydrogen; Halogen; Replace and unsubstituted C 1-C 8Alkyl, arylalkyl, nitro replaces and unsubstituted aryl hydroxyl ,-OR 3,-CO 2R 3,-O 2CR 3,-NR 32 ,-N(R 3) C(O) R 3The N(R of ,-C(O) 3) 2The R of ,-C(O) 3With their combination; R wherein 3Be hydrogen, have the alkyl and the R of 1-8 carbon atom 9SR 6R wherein 9Be C 1-C 8Alkyl.R 6Be H ,-C(O) R 7The R of ,-C(S) 7The NR of ,-C(O) 7The NR of ,-C(S) 7The OR of ,-C(S) 7,-C(O) (OR) 7, R wherein 7Be zero, C hydrogen or replacement or unsubstituted 1-C 8Alkyl.And to contain the quaternary nitrogen phosphinic acid compounds be sulphur when replacing when one, preferred R 6Be H ,-C(S) R 7Or-C(O) R 7
But, when n=0 and Q are oxygen, sulphur or nitrogen, R 5Be to be selected from hydrogen, R 9SR 6Or has an alkyl of 1 to 8 carbon atom.
Preferred R 1Be to be selected from SR 6, R 9SR 6, hydrogen, chlorine, methyl, ethyl, hydroxyl, unsubstituted amino, (N-methyl) amino, (N, N-dimethyl) amino ,-CO 2H and its pharmaceutical salts ,-CO 2CH 3With-CONH 2Preferred R 1Be to be selected from SR 6, R 9SR 6, hydrogen, methyl, chlorine, amino, and hydroxyl.Further preferred R 1Be SR 6, R 9SR 6, hydrogen, hydroxyl, or amino.
Heterocyclic group in the The compounds of this invention can be unsubstituted or independently by one or more substituting group (R on carbon atom 2) replace.R 2Group can be on same carbon atom, or on the different carbon atoms of heterocyclic group.
Therefore, R 2Group is the substituting group on one or more carbon atoms of heterocyclic group, is independently selected from N +(R 8) 3; SR 6; R 9SR 6; Hydrogen; Hydroxyl; Halogen; Has 1 to 8 alkyl on the carbon atom;-OR 3;-CO 2R 3;-O 2CR 3;-NR 32;-N(R 3) C(O) R 3;-C(O) N(R 3) 2;-C(O) R 3; Nitro; Aralkyl; Replace and unsubstituted aryl, and their combination; R wherein 3Be hydrogen, replacement or unsubstituted alkyl or R 9SR 6
Preferred R 2Substituting group is to be independently selected from N +(R 8) 3; SR 6, R 9SR 6, hydrogen, methyl, ethyl, hydroxyl, unsubstituted amino, (N-methyl) amino, (N, N-dimethyl) amino, chlorine, methoxyl group, oxyethyl group, nitro ,-CO 2H ,-CO 2CH 3,-CONH 2And their combination.Preferred R 2Substituting group is independently selected from SR 6, R 9SR 6, hydrogen, methyl, amino, chlorine, methoxyl group, hydroxyl and their combination.Most preferred R 2Substituting group is to be independently selected from R 9SR 6, SR 6, hydrogen, amino, and methyl.
R 5Be selected from following one group: hydrogen; Halogen; Replace or unsubstituted alkyl with 1 to 8 carbon atom; R 9SR 6; Hydroxyl and amino.When n=0 and Q are oxygen, sulphur or ammonia, R 5Be selected from following one group: hydrogen replaces or unsubstituted alkyl or R with 1 to 8 carbon atom 9SR 6
Each R 8Group is independently selected from following one group: zero, and the alkyl with 1-35 carbon replacement or unsubstituted; Phenyl, benzyl, or R 9SR 6In this general formula, R 8Substituting group make the nitrogen heteroatom of Z group quaternized (this moment Y=N +(R 8) 2).As previously mentioned, the Z group can be a carbocyclic ring or a heterocycle, and can be saturated, and is unsaturated or fragrant.Whether heterocycle Z group is saturated, and unsaturated or fragrant will determine R 8It is quaternized whether substituting group needs nitrogen heteroatom, at this moment Y=N +(R 8) 2When the Z group is a unsaturated or fragrant monocycle or encircles heterocyclic group more, this heterocyclic nitrogen can only be by a R 8Substituting group is quaternized.Therefore, when the Z group is a unsaturated or fragrant monocycle or when encircling heterocyclic group more, a R 8Group can be zero.When the Z group is a saturated monocycle or when encircling heterocyclic group, this heterocyclic nitrogen is former in two R more 8Substituting group is quaternized.Therefore, when the Z group is a saturated monocycle or when encircling heterocyclic group more, none R 8Can be zero, so that make the heterocyclic nitrogen atom quaternized.At least one Y or R as mentioned above 2Must contain a quaternary nitrogen atoms, therefore working as Y is (C(R 1) 2The time, at least one R 2Must be N +(R 8) 3Introduce a R at nitrogen heteroatom 8Group can form suitable to a R 2Substituting group or Y contain the quaternary nitrogen group.
Be applicable to preferred R in the The compounds of this invention of treatment or prevention calcium and phosphate metabolism disorder 8Be replacement or unsubstituted alkyl and R with 1-10 carbon 9SR 6Be applicable to treatment or prevention tartar, preferred R in the The compounds of this invention of dental plaque and gingivitis 8It is the alkyl that does not replace or replace with 10-20 carbon.
And in aforesaid general formula, when m=0 and Q were oxygen, sulphur or nitrogen, the combining to be preferably as follows of Q group and nitrogen heterocyclic ring (Z) group stated qualification.The Q group links with heterocycle on carbon atom, and directly is not connected with assorted ring nitrogen.
Preferred diphosphine acyl pyridine compound of the present invention can have following general formula:
Figure 931082781_IMG7
Also preferably connecting chain has a heteroatomic diphosphine acyl pyridine compound, also, and Q=S, O, or NR 1
Figure 931082781_IMG9
Z is that the preferred compound of the present invention of ring heterocyclic more than comprises the compound with following general formula:
Figure 931082781_IMG11
The compounds of this invention also can have following general formula:
Figure 931082781_IMG13
The concrete example of The compounds of this invention comprises:
2-(2-hydroxyl-2,2-two phosphono ethyls)-1,1-lutidine salt compounded of iodine;
3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline iodide;
3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline oxyhydroxide;
3-(2,2-two phosphono ethyls)-1-ethylpyridine muriate;
3-(2,2-two phosphono ethyls)-1-(2-mercapto ethyl) pyridinium chloride;
2-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline oxyhydroxide;
3-(3-hydroxyl-3,3-two phosphono ethyls)-1-picoline oxyhydroxide;
3-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine iodide salt;
3-(2,2-two phosphono ethyls)-1-heptyl pyridinium chloride;
3-(2,2-two phosphono ethyls)-1-picoline muriate;
3-(2,2-(phosphonomethyl) phosphino-ethyl)-1-picoline iodide;
3-(2-phosphono-2-alkylsulfonyl ethyl)-1-picoline muriate;
3-(2-carboxyl-2-phosphonoethyl)-1-picoline muriate;
2-two phosphono methyl isophthalic acids, 1-lupetidine muriate;
3-two phosphono methyl isophthalic acids, 1-lupetidine muriate;
4-two phosphono methyl isophthalic acids, 1-lupetidine muriate;
2-(2,2-two phosphono ethyls)-1,1-lupetidine muriate;
3-(2,2-two phosphono ethyls)-1,1-lupetidine muriate;
4-(2,2-two phosphono ethyls)-1,1-lupetidine muriate;
2-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
3-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
4-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
2-(2,2-two phosphonos ethyl-1-(2-mercaptoethyl) ethyl] :-1,1-lupetidine muriate;
3-(2,2-two phosphonos ethyl-1-(3-mercaptoethyl) ethyl] 1,1-lupetidine muriate;
4-(2,2-two phosphonos ethyl-1-(2-mercaptoethyl) ethyl] 1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine muriate;
3-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine muriate;
4-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-1,1,3-trimethyl-piperidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-1,1,5-trimethyl-piperidine muriate;
2-(2,2-two phosphono ethyls)-1,1,3-trimethyl-piperidine muriate;
2-(2,2-two phosphono ethyls)-1,1,5-trimethyl-piperidine muriate;
2-(3,3-two phosphono propyl group)-1,1-lupetidine muriate;
3-(3,3-two phosphono propyl group)-1,1-lupetidine muriate;
4-(3,3-two phosphono propyl group)-1,1-lupetidine muriate;
2-(3,3-two phosphonos-3-hydroxypropyl)-1,1-lupetidine muriate;
3-(3,3-two phosphonos-3-hydroxypropyl)-1,1-lupetidine muriate;
4-(3,3-two phosphonos-3-hydroxypropyl)-1,1-lupetidine muriate;
2-(2,2-two phosphono propyl group)-1,1-lupetidine muriate;
3-(2,2-two phosphono propyl group)-1,1-lupetidine muriate;
4-(2,2-two phosphono propyl group)-1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-amino-ethyl)-1,1-lupetidine muriate;
3-(2,2-two phosphonos-2-amino-ethyl)-1,1-lupetidine muriate;
4-(2,2-two phosphonos-2-amino-ethyl)-1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-amino-ethyl)-1,1,3-lupetidine muriate;
2-(2,2-two phosphonos-2-amino-ethyl)-1,1,3-lupetidine muriate;
3-(2,2-two phosphonos-2-amino-ethyl)-1,1,5-lupetidine muriate;
2-(2,2-two phosphonos-2-(methylamino) ethyl)-1,1-lupetidine muriate;
2-(4,4-two phosphonos-4-hydroxybutyl)-1,1,3-lupetidine thing;
2-(4,4-two phosphonos-4-hydroxybutyl)-1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-3-carboxyl-1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-5-carboxyl-1,1-lupetidine muriate;
2-(2,2-two phosphono ethyls)-1-methylpyrimidine muriate;
4-(2,2-two phosphono ethyls)-1-methylpyrimidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-1-methylpyrimidine muriate;
4-(2,2-two phosphonos-2-hydroxyethyl)-1-methylpyrimidine muriate;
2-(3,3-two phosphono propyl group)-1-methylpyrimidine muriate;
4-(3,3-two phosphono propyl group)-1-methylpyrimidine muriate;
2-(3,3-two phosphonos-1-hydroxypropyl)-1-methylpyrimidine muriate;
4-(3,3-two phosphonos-1-hydroxypropyl)-1-methylpyrimidine muriate;
2-(2,2-two phosphonos-2-aminopropyl)-1-methylpyrimidine muriate;
3-[(two phosphono methyl) oxo]-1,1-lupetidine muriate;
4-[(two phosphono methyl) oxo]-1,1-lupetidine muriate;
3-[(2,2-two phosphono ethyls) oxo]-1,1-lupetidine muriate;
4-[(2,2-two phosphono ethyls) oxo]-1,1-lupetidine muriate;
3-[(two phosphono methyl) sulfo-]-1,1-lupetidine muriate;
4-[(two phosphono methyl) sulfo-]-1,1-lupetidine muriate;
Salt that they are medicinal and ester.
Preferred compound of the present invention comprises:
3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline iodide;
3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline oxyhydroxide;
3-(2,2-two phosphono ethyls)-the 1-(2-mercaptoethyl) pyridinium chloride;
2-(2-hydroxyl-2,2-two phosphono ethyls)-1,1-lupetidine salt compounded of iodine;
3-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine salt compounded of iodine;
3-(2,2-two phosphono ethyls)-1-heptyl piperidines muriate;
3-(2,2-two phosphono ethyls)-1-methyl piperidine muriate;
2-(2,2-two phosphono ethyls)-1,1-lupetidine muriate;
3-(2,2-two phosphono ethyls)-1,1-lupetidine muriate;
4-(2,2-two phosphono ethyls)-1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine muriate;
3-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine muriate;
4-(2,2-two phosphonos-2-hydroxyethyl)-1,1-lupetidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-1,1,3-trimethyl-piperidine muriate;
2-(2,2-two phosphonos-2-hydroxyethyl)-1,1,5-trimethyl-piperidine muriate;
2-[2,2-two phosphonos-1-(2-mercaptoethyl) ethyl]-1,1-lupetidine muriate;
3-[2,2-two phosphonos-1-(3-sulfydryl propyl group) ethyl]-1,1-lupetidine muriate;
2-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
3-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
4-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
Most preferred compound of the present invention comprises:
3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline iodide;
3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline oxyhydroxide;
3-(2,2-two phosphono ethyls)-the 1-(2-mercaptoethyl) pyridinium chloride;
2-[2,2-two phosphonos-1-(2-mercaptoethyl) ethyl]-1,1-lupetidine muriate;
3-[2,2-two phosphonos-1-(3-sulfydryl propyl group) ethyl]-1,1-lupetidine muriate;
2-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
3-(2,2-two phosphono ethyls)-1-methyl isophthalic acid-(2-mercaptoethyl) piperidines muriate;
For the evaluation of measuring pharmacologically active, use the known various measuring methods of those of skill in the art in this area to carry out the test of phosphinic acid compounds in animal body.Therefore, use a kind of measuring method of measuring these compounds inhibition bone resorption abilities that is designed for can detect fracture assimilating activity in the body easily, the feature of said bone resorption is unusual calcium and phosphate metabolism.A kind of like this test as known in the art is the Schenk model trial.Another kind of useful test known in the art is that to also have a kind of useful test be external hydroxyapatite crystal growth inhibition test in the adjuvant arthritis test.These and other be applicable to that the test of measuring pharmacologically active is disclosed in and/or referring to people's such as shinoda works, Calcified Tissue International, 35, pp 87-99(1983); Schenk et al., Calcified Tissue Resarch, 11, pp 196-214(1973); Russell et al., Calcified Tissue Research, 6, pp 183-196(1970); Muhlbauer and Fleisch, Mineral Electrolyte Metab., 5, pp 296-303(1981); Nancollas et al., Oral Biol., 15,731(1970); The United States Patent (USP) 3,683,080 of the Francis that on August 8th, 1972 authorized; The United States Patent (USP) 4,134,969 of the Schmidt-Dunker that on January 16th, 1979 authorized; The open No.189 of disclosed Europe patent application on August 6 in 1986,662; The description of all these reference all is combined in herein by reference.In the embodiment of back, some these determination of pharmacological activity tests are described in more detail.
Except being used for the treatment of or preventing with abnormal calcium or phosphate metabolism is the pathological condition of feature, and The compounds of this invention also has other purposes.For example, they can be used for the formation of dental calculus on the prophylaxis of teeth (being tartar) and/or dental plaque.In addition, The compounds of this invention is considered to can be used as the bone scanning agent after with the 99m-mtc labeled.In addition, The compounds of this invention can also be used as the sequestrant of polyvalent metal ion, especially divalence (as calcium and magnesium) and trivalent (as indium) metal ion.Therefore The compounds of this invention can be used as the washing assistant of washing composition and sanitising agent or be used for treating water.They can also be as the stablizer of compound.At last, The compounds of this invention can be used the weedicide of doing the animal toxicological harmless.
Can include heterocyclic substituted according to following non-limiting example 1 to 16 preparation, contain the pharmaceutical composition of the present invention of quaternary nitrogen phosphonic acid ester.
The composition that contains the new phosphinic acid compounds that contains quaternary nitrogen
Can deliver medicine to people or other Mammalss by way of the quaternary nitrogen phosphinic acid compounds that contains that the present invention is new by various, route of administration includes, but are not limited to, oral administration and drug administration by injection (intravenously, intramuscular, intraperitoneal and subcutaneous).Use following suitable drug vehicle, the those of skill in the art in this area can easily prepare and contain new many other formulations that contain the quaternary nitrogen phosphinic acid compounds of the present invention.Consider patient's the situation of accepting, general oral dosage form is most preferred.
Term used herein " pharmaceutical composition " is meant and contains the quaternary nitrogen phosphinic acid compounds active ingredient or the combination of their mixture and pharmaceutically acceptable vehicle by a kind of safety, significant quantity.
Phrase used herein " safety; significant quantity " is meant the amount of a kind of compound or composition, this consumption can be even as big as the symptom and/or the situation of the required treatment of useful improvement significantly in correct medical care evaluation scope, but wants in a small amount to the effect (with a rational benefit/risk-benefit risks) of paying that is enough to avoid serious.The safety and the significant quantity of the active ingredient that uses in the inventive method institute pharmaceutical composition, in treatment doctor's expertise scope, can be with treatment patient's special status, treatment patient's age and physical appearance, the character of treatment, employed concrete active ingredient are followed in the severity of disease, treatment the course of treatment, used concrete medicinal vehicle and similar factor and change to some extent.
Term used herein " medicinal vehicle " comprises the known any physiology inert of those of skill in the art in this area, the material of non-pharmacologically active, it with select for use specific contain the physics of quaternary nitrogen phosphinic acid compounds active ingredient and change feature compatible.Medicinal vehicle includes, but are not limited to, polymkeric substance, resin, binder, weighting agent, tackiness agent, lubricant, antiseize paste, disintegrating agent, solvent, solubility promoter, buffering system, tensio-active agent, sanitas, sweeting agent seasonings, the dyestuff of pharmaceutical grade or pigment, and adhesion agent.
Term used herein " oral dosage form " but be meant that oral cavity by described individuality is transported to individual GI any system with described composition and gives the pharmaceutical composition of individual dispenser.Be the object of the invention, form of administration can be the dressing or the tablet of dressing not; Solution; Suspension; Or the dressing or the capsule of dressing not.
Term used herein " injection " is meant by intravenously, intramuscular, intraperitoneal or subcutaneous injection mode, and a kind of solution that contains active ingredient or emulsion are transported said solution or emulsion to the individual recycle system and can be to any pharmaceutical composition of human body or other mammlian system administrations through the skin of the said individuality that punctures.
Those of skill in the art in this area can handle following any one or the Several Factors speed that discharges of Controlling System satisfactorily:
(a) suitable active ingredient;
(b) medicinal vehicle; As long as it changes the activity that does not influence selected concrete active ingredient;
Required denseness of the accessory of (c) type of vehicle, and said vehicle and perviousness (expansion characteristics);
(d) the inner time-dependent situation of vehicle itself and/or vehicle;
(e) granular size of seed activity composition; With
(f) pH-of vehicle relies on situation.
Particularly, the different quaternary nitrogen phosphonate active ingredients that contain, as acid salt, the salt that forms with carboxyl is as an alkali metal salt, alkaline earth salt, etc., and ester, as alkyl, aryl, the solubleness of aralkyl, acidity and be easy to hydrolysis degree can be used as the guide of suitable selection.In addition, in active ingredient, add suitable reducing according to required release profile and in oral dosage form, set up suitable pH-condition.
The formulation that is particularly suitable for anti-calculus of the present invention and the administration of antiplaque composition is: dentifrice agent (comprising toothpaste and tooth powder), and collutory and sprays, dentistry solution, chewing-gum and mouth are chewed glue.The formulation of preferably combination of the present invention is a dentifrice agent.The composition of toothpaste generally comprises a kind of tooth abrasive (10% to 50%), a kind of tensio-active agent (0.5% to 10%), a kind of thickening material (0.1% to 5%), a kind of wetting Agent for Printing Inks (10% to 55%), a kind of seasonings (0.04% to 2%), a kind of sweeting agent (0.1% to 3%), a kind of tinting material (0.01% to 0.5%), and water (2% to 45%).Dentifrice agent can also comprise a kind of safety, and the fluoride ion source of significant quantity generally is a kind of water soluble fluoridized compounds.This water soluble fluoridized compounds generally content in the present composition is the fluoride concn that is enough to reach 0.005% to 2.0% weight ratio.Preferred fluoride source is a Sodium Fluoride, acidifying phosphoric acid salt fluorochemical, and sodium monofluorophosphate.The people's such as Widder that on July 18th, 1972 published United States Patent (USP) 3,678,154 discloses this salt and other salt, and reference is in conjunction with in the literary composition.
Other preferred composition of the present invention is mouth wash shua and oral spray.The component of this mouth wash shua and oral spray comprises water (45% to 95%), ethanol (0% to 25%), wetting Agent for Printing Inks (0% to 50%), tensio-active agent (0.01% to 7%), seasonings (0.04% to 2%), sweeting agent (0.1% to 3%) and tinting material (0.001% to 0.5%).This mouth wash shua and oral spray can also comprise one or more anticalculus agent (0.15% to 3%), and antiplaque agent (0.1% to 5%).
Other preferred composition of the present invention is a dentistry solution.The component of this dentistry solution generally comprises water (about 90% to 99%), sanitas (0.01% to 0.5%), thickening material (0% to 5%), seasonings (0.04% to 2%), sweeting agent (0.1% to 3%), and tensio-active agent (9% to 5%).
The chewing-gum composition generally comprises one or more of following component: water (0% to 99%), a kind of wetting Agent for Printing Inks such as glycerine (0% to 99%), a kind of thickening material (0.1% to 5%), a kind of seasonings (0.04% to 2%) and a kind of sweeting agent (0.01% to 0.5%).
The Chewing gum composition generally comprises one or more of following component: gel matrix (50% to 90%), seasonings (0.04% to 2%) and sweeting agent (0.01% to 20%).
As mentioned above, medicinal vehicle includes, but are not limited to, resin, weighting agent, tackiness agent, lubricant, solvent, antiseize paste, disintegrating agent, solubility promoter, tensio-active agent, sanitas, sweeting agent, seasonings, buffering system, the dyestuff of pharmaceutically grade or pigment, and adhesion agent.
Preferred solvent is a water.
Be applicable to that seasonings of the present invention comprises that seasonings that is disclosed in down in the document:
Remington ' s Pharmaceutical Sciences, the 18th edition, Mack publishing company, nineteen ninety, 1288-1300 page or leaf.By this paper with reference to combination.Be applicable to that pharmaceutical composition of the present invention generally contains 0 to 2% seasonings.
Being used for the treatment of or preventing the special preferred flavorings of the The compounds of this invention of tartar and dental plaque is menthol, wintergreen oil, spearmint oil or Syzygium aromaticum stem oil.The content of seasonings in anticalculus agent and antiplaque composition generally is 0% to 3%, preferred 0.04% to 2% weight ratio.
Comprise described in the following document those to being used for those dyestuffs of the present invention or pigment: Handbook of Pharmaceutical Excipients, PP.81-90,1986. authors: American Pharmaceutical Association ﹠amp; The Pharmaceutical Society of Great Britain, reference also is combined in herein.Pharmaceutical composition of the present invention generally contains dyestuff or the pigment of 0-2%.
Preferred solubility promoter includes, but are not limited to ethanol, glycerine, propylene glycol, polyoxyethylene glycol.Pharmaceutical composition of the present invention contains the 0-50% solubility promoter.
Preferred buffering system includes, but not limited to acetate, boric acid, and carbonic acid, phosphoric acid, succsinic acid, toxilic acid, tartrate, citric acid, acetate, phenylformic acid, lactic acid, R-Glyceric acid, glyconic acid, pentanedioic acid and L-glutamic acid are with their sodium, potassium and ammonium salt.Particularly preferably be phosphoric acid, tartrate, citric acid and acetate and salt thereof.Pharmaceutical composition of the present invention generally contains the 0-5% buffering system.
Preferred surfactants includes, but are not limited to, polyoxyethylene dehydration sorb (sugar) alcohol fatty acid ester, polyoxyethylene-alkyl ester, sucrose monoester and lanolin ester and ether, alkylsulfonate, sodium soap, potassium and ammonium salt.Pharmaceutical composition of the present invention comprises the 0-2% tensio-active agent.Be used for the treatment of or prevent the preferred surfactant of the present composition of tartar and dental plaque to comprise the tensio-active agent of those reasonably stability and foaming in the pH scope, comprise non-soap anionic, non-ionic, zwitterionic and amphoteric organic detergent.Many suitable surfactivitys are disclosed in the United States Patent (USP) 4,051,234 of authorizing people such as Gieske on September 27th, 1977 and authorized Agricola on May 25th, 1976, Briner, Granger; The United States Patent (USP) 3,959,458 of Widder, these two pieces of patents are combined in herein by reference.This tensio-active agent generally content in the present composition is 0% to 10%, preferred 0.2% to 5%.Tensio-active agent also can as solubilizing agent with help to keep the indissoluble composition as, some seasonings is in dissolved state.The tensio-active agent that is applicable to this purpose comprises Spheron MD 30/70 and polyoxy polymkeric substance (Polyoxamers).
Preferred sanitas includes, but not limited to phenol, the alkyl ester of P-hydroxybenzoic acid, adjacent phenyl benzene is expected phenylformic acid and salt thereof, boric acid and salt thereof, Sorbic Acid and salt thereof, chlorobutanol, phenylcarbinol, thiomersal(ate), phenylmercury acetate and Phenylmercurinitrate, Nitromersol, Zephiran chloride, pyrisept, para methyl paraben, and propylparaben.Particularly preferably be benzoic salt, pyrisept, nipagin and propylparaben.The present composition generally comprises the 0-2% sanitas.
Preferred sweeteners includes, but not limited to sucrose, glucose, and asccharin, sorb (sugar) alcohol, mannitol, and aspartame particularly preferably are sugarcane and asccharin.Pharmaceutical composition of the present invention comprises the 0-5% sweeting agent.
Preferred adhesion agent includes, but not limited to methylcellulose gum, cellulose sodium carboxymethyl, Vltra tears, hydroxypropylcellulose, sodiun alginate, carbon polymers (Carbomer), polyvinylpyrrolidone, Acacia, guar gum, xanthan gum (xanthan gum) and tragacanth gum.Particularly preferably be methylcellulose gum, carbon polymers (carbomer), xanthan gum (xanthan gum), guar gum, polyvinylpyrrolidone, Xylo-Mucine, and neusilin.The present composition comprises the 0-5% adhesion agent.
Preferred weighting agent includes, but not limited to lactose, mannitol, Sorbitol Powder, ternary calcium phosphate, secondary calcium phosphate, sompressible sugar, starch, calcium sulfate, dextrorotation and Microcrystalline Cellulose.The present composition comprises the weighting agent of 0-75%.
Preferred lubricant includes, but not limited to Magnesium Stearate, stearic acid, talcum powder.Pharmaceutical composition of the present invention comprises the 0.5-2% lubricant.
Preferred antiseize paste includes, but not limited to talcum powder and silica dioxide gel.Composition of the present invention comprises the antiseize paste of 1-5%.
Preferred disintegrating agent includes, but not limited to starch, sodium starch glycolate, cross-linked polyvinylpyrrolidone (Crospovidone), croscarmellose sodium (Croscarmelose Sodium), and Microcrystalline Cellulose.The disintegrating agent of pharmaceutical composition bag 4-15% of the present invention.
Preferred adhesive includes, but not limited to Acacia, tragacanth gum, hydroxypropylcellulose, pregelatinised starch, gelatinum, polyvinylpyrrolidone, hydroxypropylcellulose, Vltra tears, methylcellulose gum, sugar soln, as sucrose and Sorbitol Powder, and ethyl cellulose.Composition of the present invention comprises the 1-10% tackiness agent.
When preparation is used for the treatment of and prevent the oral composition of dental plaque and tartar, need to add tackiness agent and/or thickening material, especially in dentifrice composition, add.Preferred adhesive and thickening material for example comprise, carboxy vinyl polymer, and polysaccharide glue such as xanthan gum, carrageenin (Carrageenan), the water-soluble salt of Natvosol and ether of cellulose such as Xylo-Mucine and carboxymethyl hydroxyethyl cellulose are received.Nature glue is as thorn Chinese parasol glue, and Sudan Gum-arabic and tragacanth gum also can use.Available neusilin glue or pulverizing silicon-dioxide as the part thickening material with the further structure of improving.The general content of these tackiness agents and thickening material is 6%, preferred 0.1% to 5% weight part.
Another selectivity composition of preparation oral composition is a wetting Agent for Printing Inks.The effect of wetting Agent for Printing Inks be when preventing that dentifrice composition is in being exposed to air sclerosis and give collutory and dentifrice composition with the oral cavity moist feeling.Some Humectant brings the ideal sweet taste also can for mouth wash shua and dentifrice composition.Calculate by pure heat preserving agent, the content of wetting Agent for Printing Inks in composition generally accounts for 0% to 70%, preferred 2% to 55% weight part.Suitable Humectant comprises edible polyvalent alcohol such as glycerine, sorbyl alcohol, Xylitol, polyoxyethylene glycol, and propylene glycol, especially sorbyl alcohol and glycerine.
In toothpaste of the present invention, also opalizer can be used so that toothpaste is opaque.Suitable opalizer comprises that titanium dioxide and some friction agent comprise, as neusilin.
The preferred tooth that is used to prepare dentifrice agent comprises with abrasive, for example, gluey and sedimentary silicon-dioxide, lime carbonate, dicalcium orthophosphate dihydrate, Calcium Pyrophosphate, tricalcium phosphate, many calcium metaphosphates, insoluble many sodium-metaphosphates, the specific condensation product of hydrated aluminum oxide and resinousness abrasives such as urea and formaldehyde, authorize material in people's such as Cooley the United States Patent (USP) 3,070,510 on December 25th, 1962 with other materials such as those, by with reference to being bonded to herein, also can use the mixture of friction agent.
Various types of silica dental can provide special cleaning of teeth and polishing effect with abrasive, and not excessive damage enamel or dentine.Therefore, they are preferred in the present invention.
Silicon-dioxide polishing material used in the present invention and other abrasives, average granular size between 0.1 to 30 micron, preferred 5 to 15 microns.The silicon-dioxide abrasive can be sedimentary silicon-dioxide or dioxide/silica gel such as silica xerogel, sees the United States Patent (USP) 3,538,230 of authorizing people such as Pader on March 2nd, 1970 and the United States Patent (USP) 3,862.307 of authorizing Di Giulio on June 21st, 1975.These two pieces of documents are all by this paper reference and combination.On the preferred market with trade(brand)name Syloid The W.R.Grace ﹠amp that sells; Company, the silica xerogel that Davidson Chemical Division produces.The preferred precipitated material comprises that J.M.Huber Corporation is with trade(brand)name Zeodent
Figure 931082781_IMG15
The product of selling, especially name is called Zeodent 119 silicon-dioxide.The description of these silicon-dioxide abrasives seen authorize the United States Patent (USP) 4,340,583 of Wason July 20 nineteen eighty-two, by with reference to incorporated herein.
Can use the mixture of abrasive.The content range of abrasive is to be that its scope of toothpaste is about 6% to 70% as dentifrice agent in the composition described herein, and is preferred 15% to 50%, if composition is a tooth powder, can use high level, 90%.
Pharmaceutical composition of the present invention can contain the The compounds of this invention of 0.1% to 99.9% weight part.Be used for the treatment of or prevent that the pharmaceutical composition of osteoporosis and sacroiliitis (comprising rheumatoid arthritis and osteoarthritis) from preferably containing the The compounds of this invention of about 20% to 80% weight part.
Therefore, be used for the treatment of or the pharmaceutical composition of the present invention of preventing osteoporosis and sacroiliitis (comprising scorching rheumatic arthritis and osteoarthritis) comprises that 15-95%'s contains quaternary nitrogen phosphonate (ester) compound activity composition or their mixture; The seasonings of 0-2%; The solubility promoter of 0-50%; The 0-5% buffering system; The 0-2% tensio-active agent; The 0-2% sanitas; The 0-5% sweeting agent; The 0-5% adhesion agent; The 0-75% weighting agent; The 0.5-2% lubricant; The antiseize paste of 1-5%; The 4-15% disintegrating agent; With the 1-10% tackiness agent.
To be used for treatment or prevent that the present composition of tartar and dental plaque from preferably containing the aqueous solution of The compounds of this invention.This composition typically contains 0.5% to 10% weight part, preferred 0.1% to 5% weight part and the The compounds of this invention of 0.5% to 3% weight part most preferably.For the dentilave preparation, the most preferable concentrations scope of The compounds of this invention is 1% to 2% weight part.
Suitable pharmaceutical compositions is described in embodiment 19 to 21 to some extent.Suitable composition for tooth is described in the embodiment 22 to 23 of this paper.Can change the non-limiting example of this paper within those of skill in the art's the limit of power in the art and obtain a kind of pharmaceutical composition of relative broad range.
To determine how to select to contain the pharmaceutical excipient that the quaternary nitrogen phosphinic acid compounds is used in combination according to the administering mode of phosphinic acid compounds with the present invention.If this compound is a drug administration by injection, preferred pharmaceutical carrier is a sterile saline, and its pH value will transfer to about 7.4.However, the preferred modes of phosphinic acid compounds of the present invention is an oral administration, and preferably unit dosage form is tablet, capsule etc., wherein contains the phosphinic acid compounds of the present invention of about 0.1mg phosphorus to about 600mg phosphorus.The pharmaceutical carrier that is suitable for preparing the unit dosage form of oral administration is known in the art.This selection also will be depended on other auxiliary consideration such as taste, price, and stability in storage, and this is not crucial for the object of the invention, and the those of skill in the art in this area are not difficult to select.
This term used herein " mg phosphorus " is meant the phosphorus atom weight that is present in a certain amount of phosphinic acid compounds of the present invention.Use this unit to come the amount of used phosphinic acid compounds of the present invention in the inventive method and the pharmaceutical composition is carried out stdn.For example, 3-(2,2-two phosphono ethyls)-the 1-(2 mercaptoethyl) molecular weight of pyridinium chloride is the 363.7g/ mole, 17%(62g/ mole wherein) be to come from two contained in this molecule phosphorus atom.Therefore this compound that calculates a milligram contains 0.17mg phosphorus.So for the pharmaceutical composition of this compound for preparing a kind of 0.17mg of containing phosphorus, said composition should contain this compound of 1mg; And if gave the patient of a 50kg this compound agent administration with 0.17mg phosphorus/kg, so should be with the dosed administration of this compound of 50mg for this patient.
The pharmaceutically acceptable vehicle working concentration that is used in combination with this phosphinic acid compounds should be enough to provide an amount actual for dose relationship.The carrier total amount of preferred pharmaceutical compositions can account for 0.1% to 99.9% of total composition, and more preferably 20% to 80%.
For being the treatment of diseases and the prevention method of feature with abnormal calcium and phosphate metabolism
Another aspect of the present invention is that treatment and prevention are the method for the disease of feature with abnormal calcium and phosphate metabolism.In addition, the invention still further relates to the method for treatment and prevention tartar and dental plaque.This method comprises the phosphinic acid compounds of the present invention that uses a kind of safety and significant quantity to the human body of this treatment of needs or other Mammalss.
Preferred administering mode is an oral administration, but other known medication also allows, for example, the mucocutaneous membrane administration (as, Transdermal absorption, rectal administration etc.) and parenterai administration (as subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection etc.).Also comprise inhalation.Therefore, specific administering mode comprises.But be not limited to, oral, through skin, mucous membrane, hypogloeeis, muscle, intravenously, intraperitoneal and subcutaneous administration, and topical.
Term used herein " abnormal calcium and phosphate metabolism " is meant: (1) causes the loss of ubiquity or specificity bone with calcium and phosphoric acid salt abnormal metabolism, or in the body fluid calcium and phosphate content too high be the morbid state of feature; (2) cause or result from the morbid state of calcium and phosphoric acid salt abnormal deposition in the body.The first kind includes, but not limited to osteoporosis, and (blood calcium of malignant tumour is too high for the disease of Paget ' s), hyperthyroidism, and ectopic ossification disease and molten bone bone shift for Pei Jiteshi.Second class includes, but not limited to progressive ossifying myositis, calcinosis universalis and some chronic puzzlement disease such as sacroiliitis, (comprising scorching rheumatic arthritis and osteoarthritis), neuritis, bursitis, tendonitis and other cause involve the inflammatory diseases of organizing calcium and phosphatoptosis.
Term used herein " scorching rheumatic arthritis " is meant a kind of chronic systematicness and the arthritis disease that pathogenesis it be unclear that.It is characterized in that the damage of joint cartilage, ligament, tendon and bone.
Term used herein " osteoarthritis " is meant the non-inflammatory disease of movable joint.It is characterized in that the degeneration and the wearing and tearing of joint cartilage, and form new bone at articular surface.
Term used herein " population at risk " and the crowd of this treatment " need " are not meant if do not treat can suffer from unusual anyone of remarkable dangerous abnormal calcium and phosphate metabolism or other Mammalss and be diagnosed as and occur calcium and anyone unusual or other Mammalss of phosphate metabolism.For example, postmenopausal women; Just carrying out the people of certain steroid therapy; Use the people of some anticonvulsive drug; Be diagnosed as the trouble osteitis deformans, hyperthyroidism, the people that malignant tumour hypercalcinemia or molten bone bone shift; Be diagnosed as and suffer from one or more dissimilar osteoporotic people; Belong to known fall ill average probability crowd's the people of the osteoporosis of being significantly higher than that has, for example, the postmenopausal women, the age surpasses 65 years old the male sex, uses known people with the pharmacological agent that causes osteoporotic pair of effect; Be diagnosed as the people who suffers from progressive ossifying myositis or calcinosis universalis; Involve the other diseases of organizing calcium and phosphatoptosis with suffering from sacroiliitis, osteoarthritis, scorching rheumatic arthritis, neuritis, bursitis, tendonitis and causing.
Term used herein " safety and significant quantity " is meant the usage quantity of a kind of The compounds of this invention or composition, it is high to being enough to improve significantly the disease condition of being treated that this consumption is wanted in correct medical judgment scope, and will be low to moderate the effect (with a rational benefit/risk-benefit risks) of paying of avoiding serious of being enough to.The safe and effective amount of phosphinic acid compounds of the present invention, will be because of the special disease kind of being treated, by treatment patient's age and physical appearance, the severity of disease, the course of treatment, the character of following treatment, employed specific phosphinic acid compounds, used specific pharmaceutically acceptable carrier, and the similar factor in the treatment doctor expertise scope is different and change to some extent.The single dose scope that is used for the treatment of the method for abnormal calcium and phosphate metabolism is that 0.01mg phosphorus is to 3500mg phosphorus or 0.0002 to 70mg phosphorus/kg body weight (with the 50kg batheroom scale).Preferred single dose is that 1mg phosphorus is to 600mg phosphorus or 0.02 to 12mg phosphorus/kg body weight (with the 50kg batheroom scale).The dosage of every day can be 4 single doses.For the dosage that obtains required effect every day need be greater than 500mg phosphorus/kg, and can not produce unwanted side effect like this.Certainly can in this scope, use higher dosage because absorption is limited under the oral administration situation.
The formulation that is applicable to the The compounds of this invention of treatment or prevention tartar and dental plaque comprises dentifrice agent such as the toothpaste and the tooth powder of the The compounds of this invention that contains 0.05%-10% weight and contains the dentistry solution such as the collutory of the The compounds of this invention of 0.05-5% weight.
Following embodiment has further described and has illustrated the preferred embodiment in the scope of the invention.This embodiment to provide just in order illustrating but not to limit the present invention, and these embodiment can have many different forms under the spirit and scope of the invention situation not deviating from
Embodiment 1
Synthetic 3-(2,2-two phosphono ethyls)-1-ethylpyridine muriate
Figure 931082781_IMG17
I. Synthetic 2-[3-pyridyl ethylidene] two [phosphonic acids] tetraethyl ester
Under 0 ℃ to being dissolved in DMSO(155ml) 60% sodium hydride mineral oil (4.00g, 0.10mmol) add in the mixture be dissolved in DMSO(20ml) the tetraethyl-methylenediphosphonate (MDP) (30g, 0.10mmol).In 0 ℃ of following stirred reaction mixture 30 minutes, restir 30 minutes under room temperature then.Then this mixture is splashed into addition funnel under room temperature and is dissolved in DMSO(100ml) 3-picolyl chlorination thing (0.11mmol) in.Under room temperature, stir and reacted again 12 hours, add saturated aqueous ammonium chloride solution then reaction is extinguished.With the said reaction mixture of dichloromethane extraction, merge organic extraction, through dried over sodium sulfate, filter the decompression filter and contract.On silica gel, pass through this product of flash chromatography chromatography purification with 5% Virahol that is dissolved in methylene dichloride.
II. synthetic tetraethyl--3-(2,2-two phosphono ethyls)-the 1-ethylpyridine
To tetraethyl-2-(3-pyridyl) ethylidene-1,1-di 2 ethylhexyl phosphonic acid tetraethyl ester (1.96g, add in acetone 5.17mmol) (10ml) solution iodoethane (4.03g, 25.86mmol).Refluxed under nitrogen reacting by heating thing 24 hours.The concentrating under reduced pressure reaction mixture is developed thick slag with hexane and then with Anaesthetie Ether earlier.In this way a kind of N-ethylpyridine adducts, a kind of water absorbability orange solid (2.28g), yield 83%.
III. synthetic 3-(2,2-two phosphono ethyls)-1-ethylpyridine muriate
Under nitrogen in 6N HCl(30ml) in reflux hydrolysis phosphonic acid ester (2.18g, 4.08mmol) 12 hours.Reaction mixture.Concentrating under reduced pressure then.By with the Anaesthetie Ether development, obtain thorough clearly product.
Embodiment 2
Synthetic 3-(2,2-two phosphono ethyls)-the 1-(2-mercaptoethyl) pyridinium chloride
Figure 931082781_IMG18
I. synthetic tetraethyl--3-(2,2-two phosphono ethyls)-1-(2-ethanoyl thio-ethyl) the pyridine bromide
To previous embodiment 1(I part) in the 2-[3-pyridyl ethylidene of preparation]-1, two [phosphonic acids] tetraethyl esters of 1-(3.16g, add in acetone 8.35mmol) (20ml) solution S-ethanoyl-2-bromine sulfur alcohol (3.82g, 20.88mmol).Refluxed under nitrogen reacting by heating thing 24 hours.The concentrating under reduced pressure reaction mixture is with hexane with develop thick slag with Anaesthetie Ether then.On silica gel, be further purified this residue with 20% methyl alcohol that is dissolved in methylene dichloride by flash chromatography.This mode obtains a kind of quaternized adducts (1.69g) of faint yellow oily.
II. synthetic 3-(2,2-two phosphono ethyls)-the 1-(2-mercaptoethyl) pyridinium chloride
Under nitrogen environment in 6N HCl(35ml) in reflux (1.45g, 5.10mmol) 20 hours hydrolysis phosphonic acid esters.Cooling and concentrated reaction mixture.Can obtain this clear thorough product with the diethyl ether development.
Embodiment 3
Synthetic 3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline iodide disodium salt
Figure 931082781_IMG19
I. synthetic [1-hydroxyl-2-(3-pyridyl) ethylidene] two [phosphonic acids]
To at the bottom of the 250ml 3-neck garden and have add in the flask of a condenser and dropping funnel the 3-Pyridineacetic Acid hydrochloride (1.74g, 10mmol), phosphorous acid (2.46g, 30mmol) and the 50ml chlorobenzene.Then flask is placed boiling water bath, with dropping funnel in reaction mixture, drip phosphorus trichloride (4.0g, 30mmol).Stirred 3 hours down at 100 ℃, in this reaction process, form a kind of xanchromatic viscous oil.After 3 hours, this reaction mixture of cooling in ice bath, and incline and excessive chlorobenzene.This oil of hydrolysis spends the night in 100ml 1N HCl, and cooling leaches first crystallization and uses alcohol flushing.Filtrate is flashed to oily, and adding water dissolution in a small amount should oil.Adding ethanol makes generation send out a crystallization.Leach second batch of crystallization, and use alcohol flushing, with obtaining the 2.1g yield with first merging behind the hot water recrystallization.
II. synthetic 3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline iodide disodium salt
In being dissolved in 4.4ml 1N NaOH [1-hydroxyl-2-(3-pyridyl) ethylidene] two [phosphonic acids] (0.5g 1.77mmol) adds 14ml distilled water in the solution.Add again methyl-iodide ethanolic soln (12ml) (1.25g, 8.83mmol).The pH of reaction mixture is 6.0.Spend the night at 80 ℃ of heated mixt.Evaporating solvent is also developed residue with acetone.The recrystallize product obtains 3-(2-hydroxyl-2 in water and ethanol, 2-two phosphono ethyls)-1-picoline iodide disodium salt.
Embodiment 4
Synthetic 3-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline oxyhydroxide, inner salt
Figure 931082781_IMG20
To be dissolved in 6N CHl(40ml) the prepared 3-(2-hydroxyl-2 of the foregoing description 3,2-two phosphono ethyls)-(0.42g, 0.89mmol) reflux is 12 hours for 1-picoline iodide disodium salt.Reaction mixture, (iodine is removed in 5 * 40ml) washings by chloroform then.The concentrating under reduced pressure waterbearing stratum.Develop the required inner salt (255mg) that residue obtains the faint yellow solid shape, yield 85% with acetone.
Embodiment 5
2-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline oxyhydroxide, inner salt, single sodium salt
Figure 931082781_IMG21
I. synthetic [1-hydroxyl-2-(2-pyridyl) ethylidene] two [phosphonic acids]
Packing in flask at the bottom of the 250ml 3-of a band condenser and the dropping funnel neck garden, (1.74g, 10mmole), (2.46g is 30mmole) with the 50ml chlorobenzene for phosphonous acid for 2-pyridyl acetate hydrochloride.Flask is placed boiling water bath, and with dropping funnel in reaction mixture, add phosphorus trichloride (4.08g, 30mmole).Stirred 3 hours down in 100 ℃, in reaction process, form a kind of yellow viscous oil.After 3 hours, reaction mixture in ice bath, inclining excessive chlorobenzene.In oily matter, add 100ml water, this mixture reflux is spent the night.After the reflux, cooling mixture, some product begins to be precipitated out.Filter this throw out, and with washing with alcohol to obtain first crystallization.In order to obtain second batch of crystallization, make filtrate flash to oily, add less water to the oil until its dissolving.Add ethanol to bring out crystallization.Leach second batch of crystallization, and use washing with alcohol, behind the hot water recrystallize, obtain total amount 1.87g product with first merging.
II. Synthetic 2-(2-hydroxyl-2,2-two phosphono ethyls)-1-picoline oxyhydroxide, inner salt, single sodium salt
Will [1-hydroxyl-2-(2-pyridyl) ethylidene] (3.53mmol 1.0g) is dissolved in the sodium hydroxide solution and 8.8ml distilled water of 8.8ml 1N two [phosphonic acids].In this solution, add the methyl iodide be dissolved in the 18ml ethanol (17.67mmol, 1.1ml).Heating this reaction mixture down in 80 ℃ finishes until reaction.The vacuum concentration solvent, and with second alcohol and water recrystallize residue, obtain the 2-(2-hydroxyl-2 of 0.92g, 2-two phosphono ethyls)-1-picoline oxyhydroxide, inner salt, single sodium salt
Embodiment 6
3-(3-hydroxyl-3,3-two phosphono propyl group)-1-picoline hydroxide inner salt
Figure 931082781_IMG22
I. synthetic 3-(3-pyridyl) propionic acid
β-(3-pyridyl)-vinylformic acid (10g) is joined a kind of 150ml of being equipped with Glacial acetic acid, in Pa Er (Parr) the hydrogenation bottle of a 100ml dehydrated alcohol and a large spoon palladium on carbon (Palladium on Carbon) catalyzer.This solution of vibration under the hydrogen of 50Psi, and pressurize again when needed to take in until hydrogen and stop (about 3 hours).Use diatomite filtration solution, use washing with alcohol, straight empty evaporating solvent with methylbenzene azeotropic, produces the required product of white crystals shape.
II. synthetic [1-hydroxyl-3-(3-pyridyl) propylidene] two [phosphonic acids]
Add 3-pyridyl propionic acid (12.3g 79.6mmol) in flask at the bottom of the 3-of the 250ml neck garden (band condenser and dropping funnel), (19.6g is 239mmol) with the 50ml chlorobenzene for phosphoric acid.Flask is placed 100 ℃ of water-baths, and in reaction mixture, drip phosphorus trichloride (20.88ml, 239mmol).Reaction stirred 3 hours forms a kind of viscous oil, inclines this moment to chloroform, adds 100ml 1N HCl, and the mixture reflux is spent the night.Cool off this solution, leach the white precipitate of formation, and wash, produce the required product of 16.9g with ethanol and ether.
III. synthetic 3-(3-hydroxyl-3,3-two phosphono propyl group)-1-picoline oxyhydroxide, inner salt
Will [1-hydroxyl-3-(3-pyridyl) propylidene] (3.37mmol 1.0g) is dissolved in the 1N NaOH solution and 29ml distilled water of 8.4ml two [phosphonic acids].Add the methyl iodide be dissolved in the 19ml ethanol (16.83mmol, 1.05ml).80 ℃ of following reacting by heating mixture overnight.Vacuum evaporating solvent, and develop residue with acetone, recrystallization from the second alcohol and water then produces the 3-(3-hydroxyl-3 of 0.5g, 3-two phosphono propyl group)-1-picoline oxyhydroxide, inner salt.
Embodiment 7
Synthetic 3-(2,2-two phosphono ethyls)-1-heptyl pyridinium chloride
Figure 931082781_IMG23
Synthesize as follows and the preparation above-claimed cpd
I. synthetic tetraethyl--3-(2,2-two phosphono ethyls)-1-heptyl pyridine iodide
With the foregoing description 1(I part) the middle 2-[(3-pyridyl for preparing) ethylidene] two [phosphonic acids] tetraethyl ester (4.0g, 10.5mmol) solution and be dissolved in 1-iodo heptane in the dry acetonitrile (25ml) (7.14g, 31.6mmol) reflux 72 hours under nitrogen atmosphere.The vacuum-evaporation reaction mixture is to dry.Development residue twice filters in diethyl ether, and is dry in vacuum drier, obtains N-heptyl adducts (6.37g).
II. synthetic 3-(2,2-two phosphono ethyls)-1-heptyl pyridinium chloride
With N-heptyl adducts (6.20g, 10.2mmol) reflux 48 hours in 6N hydrochloric acid (62ml).This reaction mixture of vacuum-evaporation adds acetone to dry, and evaporating mixture is to dry for the second time.In ethanol, develop residue, obtain a yellow solid, filter to collect this solid, dry in vacuum drier with the diethyl ether washing, obtain two steps of 29%() N-heptyl pyridine di 2 ethylhexyl phosphonic acid (1.19g).
Embodiment 8
Synthetic 3-(2,2-two phosphono ethyls)-1-picoline muriate
Figure 931082781_IMG24
Synthesize as follows and the preparation above-claimed cpd
I. synthetic tetraethyl--3-(2,2-two phosphono ethyls)-1-picoline iodide
With the foregoing description 1, what prepare in the part I contains the 2-[(3-pyridyl) ethylidene] two [phosphonic acids] tetraethyl ester (5.0g, solution 13.2mmol), methyl iodide (5.60g, 39.5mmol) and dry acetonitrile (32ml) reflux 72 hours.The vacuum-evaporation reaction mixture adds acetone to dry, and evaporating mixture is to dry for the second time.In hexane/diethyl ether, develop crude product, under nitrogen, filter and collect product, dry in vacuum drier, obtain 5.0g N-picoline adducts.
II. synthetic 3-(2,2-two phosphono ethyls)-1-picoline muriate
(5.0g 13.1mmol) made hydrolysis of phosphonate in 48 hours to the methylated adducts of backflow N-in 6N hydrochloric acid (54ml).The vacuum-evaporation reaction mixture adds acetone to dry, and evaporating mixture is extremely dry in a vacuum for the second time.In ethanol, develop residue, obtain a solids, filter and collect.Crude product is dissolved in the water of minimum, uses activated carbon treatment, use diatomite filtration then.Pour filtrate in the ethanol this product of precipitation, filtration is collected product and is dry in vacuum drier, obtains methylated pair of phosphonic acids of N (1.05g, the productive rates in two steps are 25%).
Embodiment 9
Synthetic 3-(2-phosphono-2-methyl phosphino-ethyl)-1-picoline iodide
Synthesize as follows and the preparation above-claimed cpd
I. Synthetic 2-(3-pyridyl ethylidene) (phosphonomethyl) phospho acid triethyl ester
Use basically and previous examples 1; identical method described in the part I; methylene radical (phosphonomethyl) phospho acid triethyl ester [is pressed Henning; H.G. and Petzold; G. described preparation; see Z.Chem., Vol.5, pp 419(1965)] change into 2-(3-pyridyl ethylidene) (phosphonomethyl) phospho acid triethyl ester.
II. synthetic triethyl-3-(2-phosphono-2-methyl phosphino-ethyl)-1-picoline iodide
Under nitrogen in dry acetone (23ml) with the 2-(3-pyridyl) ethylidene (phosphonomethyl) phospho acid triethyl ester (and 2.32g, 6.64mmol) and methyl iodide (9.42g, 6.44mmol) reflux is 24 hours.The vacuum-evaporation reaction mixture adds acetone to dry, and this mixture of vacuum-evaporation for the second time obtains the methylated adducts of N-(2.60g) to dry.
III. synthetic 3-(2-phosphono-2-methyl phosphino-ethyl)-1-picoline iodide.
Reflux N-picoline adducts (2.60g, 6.20mmol) 18 hours in 6N hydrochloric acid.The vacuum-drying reaction mixture adds methyl alcohol to dry, evaporates this mixture for the second time.Crude product is dissolved in the water of minimum volume.Use filtered through silica gel then.Vacuum-evaporation aqueous solution filtrate obtains 0.5g(two productive rate 25% in step) N-picoline (phosphonomethyl) phospho acid.
Embodiment 10
Synthetic 3-(2-phosphono-2-alkylsulfonyl ethyl)-1-picoline muriate
Figure 931082781_IMG26
Synthesize as follows and the preparation above-claimed cpd
I. synthetic triethyl-2-(3-pyridyl) ethylidene-1-phosphono-1-sulphonate
40% NaH(1.10mmol under 0 ℃ of nitrogen atmosphere in oil and toluene (100ml)) adds diethoxy phosphinyl methylsulfonic acid in the mixture, ethyl ester (1.00mmol) [is pressed J.C.Carretero, Deng the described preparation of people, see Tetrahedron, Vol.43, PP.5125-5134(No.21) 1987).Stir after 30 minutes, with addition funnel under the room temperature in the toluene solution (50ml) of 3-picolyl chlorination thing (1.00mmol) the dropwise reaction mixture.Continue to stir 12 hours, reaction mixture is poured in the water into layering.Extract waterbearing stratum twice with diethyl ether, with the organic layer of saturated sodium chloride solution washing merging.By fast chromatographic product is separated with unreacted initial substance on silica gel with 10% Virahol that is dissolved in methylene dichloride.Produce a kind of faint yellow oily phosphononosulfonatecompounds.
II. synthetic triethyl-3-(2-phosphono-2-alkylsulfonyl ethyl)-1-picoline iodide
With (triethyl-2-(3-pyridyl) ethylidene-1-phosphono-1-sulphonate of a kind of containing) (5.0mmol), the solution reflux of methyl iodide (25.0mmol) and dry acetonitrile (100ml) 72 hours.This reaction mixture of vacuum-evaporation adds acetone to dry, for the second time the evaporating mixture drying.In hexane/diethyl ether, develop crude product, under nitrogen, filter and collect product, dry in vacuum drier, obtain N-picoline adducts.
III. synthetic 3-(2-phosphono-2-sulfoethyl)-1-picoline muriate
At backflow 6N HCl(10ml) in hydrolysis of N-methyl pyridinium salt (0.3mmol) 12 hours.This reaction mixture of vacuum-evaporation is to dry.Crude product is dissolved in the water of minimum, uses activated carbon treatment, use diatomite filtration then.Pour filtrate in ethanol precipitated product, filter the collecting precipitation thing, dry in vacuum drier, obtain 3-(2-phosphono-2-sulfoethyl)-1-picoline muriate.
Embodiment 11
Synthetic 2-(2-hydroxyl-2,2-two phosphono ethyls)-1,1-lutidine iodide
I. synthetic [1-hydroxyl-2-(2-piperidyl) ethylidene] two [phosphonic acids] single sodium salt
With the foregoing description 5, prepare in the part I [1-hydroxyl-2-(2-piperidyl) ethylidene] two [phosphonic acids] (2.5g 0.0088mole) joins in the water of 50ml, transfers pH to 6.0 with 50%NaOH.This solution is joined in the Pa Er hydrogenation bottle of a 500ml, add the 10%Pd/C catalyzer of about 1g.Parr bottle is placed on the Pa Er hydrogenation unit, be forced into the H of 45psi 2Gas.After 4 hours, add more catalyzer.Pressure is recalled to 45psi, make it reaction and spend the night.Use diatomite filtration solution, wash with water, be evaporated to thorough clearly oily then.In oil, add ethanol (30ml), relax reflux mixture 48 hours, oily matter is changed into the powdery white precipitate.Filter, and use washing with alcohol.
II. Synthetic 2-(2-hydroxyl-2,2-two phosphono ethyls)-1,1-lutidine iodide salt
Will [1-hydroxyl-2-(2-pyridyl) ethylidene] two [phosphonic acids] single sodium salt (3.5mmol) be dissolved in a kind of DMSO(10ml) and the mixture of water (50ml) in.In this solution, add methyl-iodide (35.0mmol), heated this solution 3 days in refluxed under nitrogen.The concentrating under reduced pressure reaction mixture, recrystallize comes the purifying quaternized products from water and Virahol.
Embodiment 12
Synthetic 3-[2,2-two phosphonos-2-hydroxyethyl]-1,1-lutidine iodide
Figure 931082781_IMG28
I. synthetic [1-hydroxyl-2-(3-piperidyl) ethylidene] two [phosphonic acids] single sodium salt
With the foregoing description 3, prepare in the part I [1-hydroxyl-2-(3-pyridyl) ethylidene] two [phosphonic acids] (2.0g 0.0071mole) joins in the 50ml water, transfers pH to 6.0 with 50%NaOH.This solution is joined in the 500ml Pa Er hydrogenation bottle, and add the 10% Pd/C catalyzer of about 1g.Parr bottle is placed on the Pa Er hydrogenation unit, be forced into the H of 45psi 2Gas.After 4 hours, add more catalyst, pressure is recalled to 45psi, make it reaction and spend the night.Use diatomite filtration solution, wash with water, be evaporated to limpid oily.In oil, add ethanol (30ml).Gentle reflux mixture 1 hour changes into powdery with oily matter, white precipitate.Filter, use washing with alcohol.
II. synthetic 3-[2,2-two phosphonos-2-hydroxyethyl]-1,1-lupetidine iodide
Use and the foregoing description 11, essentially identical method described in the part II will [1-hydroxyl-2-(3-piperidyl) ethylidene] two [phosphonic acids] single sodium salt changes into 3-[2,2-two phosphonos-2-hydroxyethyl]-1,1-lupetidine iodide.
Embodiment 13
Synthetic 3-(2-hydroxyl-2-phosphonoethyl)-1-picoline muriate
By following synthetic and preparation above-claimed cpd.
I. synthetic trimethylammonium 2-phosphono-3-(3-pyridyl) propionic ester (propanoate)
To the trimethyl-phosphine ethyl sodio acetoacetic ester solution 8.09ml(0.050mole that is dissolved in the anhydrous DMSO of 50ml) in reduce foam ground lentamente as far as possible and add 2.00g(0.050mole) NaH(with 60% in mineral oil) the preparation solution A.This reaction mixture is a kind of yellow solution.(all above-mentioned steps all are to finish in the glassware that oven drying is crossed in envrionment temperature under nitrogen).
8.20g(0.050mole in being dissolved in the 50ml anhydrous dimethyl sulphoxide) add down slowly (in 5 minutes to reduce foam as far as possible) 2.0g(0.050mole in nitrogen in the 3-picolyl chlorination thing hydrochloride mixture) NaH(with 60% in mineral oil).Reaction stirred 75 minutes.In reaction mixture, add solution A in during 40 minutes.Stirred gained solution at ambient temperature 18 hours.Vacuum is gone down and is desolventized.Obtain a kind of viscosity reddish-brown material.Said material is dissolved in the saturated NH of 100ml 4In the Cl solution (aqueous solution) and with 3 * 100ml dichloromethane extraction.The united extraction thing is used MgSO 4Drying, the vacuum-evaporation drying obtains the oily matter of 11.3g.Hexane with 3 * 100ml extracts mineral oil from oily matter.Obtain the reddish-brown material of 9.6g.Use acetone as eluent preparation property HPLC purifying on a silicagel column, be recovered to the required product of 2.5g.
II. synthetic 3-(2-carboxyl-2-phosphonoethyl)-1-picoline muriate
2.5g(0.009mole with a kind of 5ml of being dissolved in dry tetrahydrofuran) 2-phosphono-3-(3-pyridyl) propionic acid trimethylammonium ester and 2.25ml(0.020mole) solution of methyl-iodide stirred 18 hours at ambient temperature.During this period of time form jelly.Inclining solvent, washs thick thing with the dry diethyl ether of 2 * 10ml.
This jelly is dissolved in ester hydrolysis group among the 6N HCl of 25ml, reflux gained solution 3 hours.Cooling solution, and with the CHCl of 3 * 8ml 3Extract, remove the part I 2Vacuum-evaporation water liquid layer obtains brown jelly.It is dissolved in the hot dehydrated alcohol of 20-25ml.Cooling solution, the dry acetone of adding 10-15ml.Stir at ambient temperature and formed a solid in 14 hours.Leach solid, use washing with acetone, and then wash, obtain the faint yellow solid of 2.0g with ether.Its dehydrated alcohol with 10ml stirred be further purified in 2.5 hours, filter then, use the 3ml washing with alcohol, use the 10ml washing with acetone, and then wash with ether.Obtain the 1.82g(71% yield) 3-(2-carboxyl-2-phosphonoethyl)-1-picoline muriate.
Embodiment 14
Synthetic 3-(3,3-two phosphono propyl group)-the 1-cetyl pyridinium, disodium salt
Figure 931082781_IMG30
I. synthetic [the 3-2-pyridyl) propylidene] two [phosphonic acids] tetraethyl ester
To be dissolved in the dried benzene of 200ml phenyl lithium (79ml, 1.96M is dissolved in ether, 0.155mol) is cooled to 0 ℃, be added dropwise to the 2-picoline that is dissolved in the 50ml benzene (12.3g, 0.132mol).Reaction stirred 3 hours adds two (phosphonic acids) tetraethyl esters of the vinylidene that is dissolved in 50ml benzene again.Reaction solution is warmed to room temperature, and stirs and spend the night, add 1NHCl(132ml) cooling simultaneously, layering appears.Regulate the pH to 10 of water, several times with ethyl acetate extraction.United extraction thing dried over sodium sulfate is filtered, and evaporation obtains [3-(2-pyridyl) propylidene] two [phosphonic acids] tetraethyl ester of 47.2g.7% MeOH/CHCl before using 3By this crude product of fast chromatographic partial purification.For example, divide two stratographic analysis 13.2g products to obtain the purified product of 8.2g.
II. synthetic 3-(3,3-two phosphono propyl group)-1-cetyl pyridinium iodide, tetraethyl ester
(8.2 restrain the tetraethyl-bisphosphonate that will partly prepare by the above-mentioned steps I, 20.9mmol) be dissolved in the acetonitrile of 50ml, add cetyl iodide (22g, 62.5mmol), this mixture was refluxed three days, solvent evaporated, residue is placed on the silica gel bed of 10 inch with 5% methyl alcohol/chloroform wash-out, excessive cetyl iodide is carried in first three component and being washed, in some parts, collect product, merge first three component, obtain the 5.3g product, and 8 later components obtain the 7.8g product after merging, altogether 13.1 grams.
III. synthetic 3-(3,3-two phosphono propyl group)-1-cetyl pyridinium disodium salt
With above-mentioned four esters (7.8g, 10.5mmol) reflux 2 days in the 6N of 75ml HCl.The cooling reactant is used ethyl acetate extraction.The evaporation water, add methyl alcohol once more evaporating solns obtain the product of 5.4g.Add the sodium hydroxide (17ml) of 1N and transfer pH to 7.This solution of lyophilize obtains the 3-(3 of 5.6g, 3-two phosphono propyl group)-1-cetyl pyridinium disodium salt (79%), be similar to disodium salt.
Embodiment 15
Synthetic 3-(7-two phosphono methylols)-2-methyl-2-pyridine iodide
Figure 931082781_IMG31
I. synthetic N-(2,2-diethoxy ethyl)-the N-[(3-p-methoxy-phenyl) methyl]-the 4-methyl benzenesulfonamide
Between will be in benzene (2.6 liters)-and aubepine (112g, 0.82mol) and aminoacetaldehyde diethyl acetal (115g, 0.86mmol) reflux 3 hours under nitrogen atmosphere.Decompression concentrates down to remove about 1.8 liters benzene, rest solution is joined in the Pa Erjia hydrogen tank under room temperature hydrogenation until the hydrogen (561b.) of taking in theoretical value.Use diatomite filtration solution then, concentrating under reduced pressure filtrate.The shape thing of gained is dissolved in the pyridine (1 liter), and drips that (stirred reaction mixture is 3 days under the room temperature, then concentrating under reduced pressure for 172g, pyridine solution 0.90mol) (600ml) to the anisole SULPHURYL CHLORIDE.Residue is poured in the frozen water in 0 ℃ of stirring 1 o'clock.(6 * 500ml) extract mixed solution with diethyl ether.Merge organic extraction also with saturated NaCl solution washing,, filter through dried over mgso, and concentrating under reduced pressure, a kind of yellow oil product (312g) obtained, yield 93%.
II. synthetic 7-methoxyl group isoquinoline 99.9
Have at the bottom of 2 liters of gardens of magnetic stirring bar, condenser and nitrogen inlet to one and to add N-(2 in the flask, 2-diethoxy ethyl)-and the N-[(3-p-methoxy-phenyl) methyl]-4-benzsulfamide (75g, 0.184 the 6N HCl of 1.0 liters of De dioxs and 200ml mole).Stir this slurries and refluxed under nitrogen heating 18 hours.Then reaction solution is poured lentamente into 1 liter H 2Among the O, restir 30 minutes extracts (2 * 500ml) with ether then.Transfer the pH to 8 in waterbearing stratum with ammonium hydroxide, use the dichloromethane extraction product.Merge organic extraction, through MgSO 4Drying is filtered, and evaporation obtains the oily matter of 30g.Through this crude product of stratographic analysis purifying, obtain this product (19.7g), yield 67% with 12.0% acetone that is dissolved in methylene dichloride.
III. synthetic 7-hydroxyl isoquinoline 99.9
Have magnetic stand to one and mix rod and addition funnel 2 liters, adding 19.7g(0.124 mole in the flask at the bottom of the 3-neck garden) 7-methoxyl group isoquinoline 99.9 and the anhydrous methylene chloride of 800ml.Stir this solution, in dry ice/acetone batch, be cooled to-75 ℃.Be added dropwise to the 1.0M boron tribromide 628ml(0.628mole that is dissolved in the methylene dichloride) and maintain the temperature at-75 ℃.Stir these slurries and raise the temperature to room temperature after 18 hours.Reacting slurry poured in 1 liter the frozen water, slowly stirred 1 hour.Layering occurs, with 1N NaOH the waterbearing stratum is transferred to neutrality (pH7) from acidity then.The yellow solid precipitation occurs, leach throw out, dry air obtains the yellow solid of 14.5g, 81%.
IV. synthetic 7-hydroxyl-8-nitroisoquinoline
To adding 14.5g(0.1mole in the flask at the bottom of the garden of a 300ml) 7-hydroxyl isoquinoline 99.9 and the tetramethylene sulfone of the heat of 100ml.Stir brown slurries, and add 18.6g(0.14mole in batches) nitronium tetrafluoroborate, simultaneously the cooling (ice bath).Reaction stirred 3 hours.Methyl alcohol with 100ml quenches reaction solution then, is evaporated to drying, with ether development twice, obtains a dark solid (19.0g, 100%).
V. synthetic 8-amino-7-hydroxyl isoquinoline 99.9 HCl salt
Adding 7-hydroxyl-8-nitroisoquinoline in a hydrogenation jar (28.5g, 0.15mol), 5%Pd-carbon (6.0g) and ethanol (725ml).Take in for slurries hydrogenation (40psi) stops to hydrogen.Use the diatomite filtration reaction mixture then, concentrating under reduced pressure filtrate.Residue is dissolved in the methyl alcohol, adds ethereal hydrochloric acid (etheric-HCl), be settled out a kind of HCl salt product (19g), yield 65%.
IV. synthesizing chlorinated 7-hydroxyl-8-isoquinoline 99.9 diazonium salt
In 0 ℃ of 8-amino-7-hydroxyl isoquinoline 99.9 HCl salt (4.94g, 0.25mmol) middle a kind of nitrite tert-butyl (17.46ml), solution of ethanol (790ml) and water (58ml) of dripping in being dissolved in ethanol HCl.After finishing liquid feeding, 0 ℃ of following restir solution 2 hours.Add diethyl ether (2 liters) precipitated product from reaction mixture.Filter to collect product, and use diethyl ether drip washing, obtain yield and be 50% required product 2.6g.
VII. Synthetic 2-pyridine-7-carboxylic acid, methyl esters
With 275 watts fluorescent lamps 0 ℃ down irradiation 7-hydroxyl-8-isoquinoline 99.9 diazonium muriate (0.50g, 2.4mmole) and sodium bicarbonate (the vacuum-evaporation reaction mixture is to drying for 302mg, absolute methanol solution 3.6mmol) (650ml) 3 hours.Thick slag is soluble in water, use the dichloromethane extraction product.The organic extraction that merges through dried over mgso, is filtered, and concentrating under reduced pressure, a kind of orange solid product (210mg) obtained, yield 50%.
VIII. synthesizing dihydro-2-pyridine-7-carboxylic acid, methyl esters
In a kind of hydrogenation bottle, pack into 2-pyridine-7-carboxylic acid methyl esters (0.8g, 4.57mmol), 5% palladium-carbon (2.0g, wet) and methyl alcohol (125ml).Take in for slurries hydrogenation (40psi) stops until hydrogen.Use the diatomite filtration reaction mixture, be evaporated to drying then, obtain product (430mg), yield 53%.
IX. synthesizing dihydro-2-pyridine-7-carboxylic acid, HCl salt
To be dissolved in 1N NaOH(3.1ml) and methyl alcohol (30ml) in dihydro-2-pyridine-7-carboxylic acid methyl esters (0.53g is 3.0mmol) 58 ℃ of down heating 2.5 hours.Vacuum evaporated solution stirs resulting residue, precipitated product to dry in ethanol HCl.Filter and collect required product.
X. synthetic [1-hydroxyl-(dihydro-2-pyridine-7-yl) methylene radical] two [phosphonic acids]
To phosphorus trichloride (1.19g adds a kind of dihydro-2-pyridine-7-carboxylic acid in 8.63mmol), HCl salt (0.54g, 2.88mmol), phosphoric acid (708mg, 8.63mmol) and the slurries of chlorobenzene (10ml).Stirred reaction mixture, and under 105 ℃, heated 4 hours.Cooling mixture is to room temperature then, and inclining chlorobenzene.In thick slag, add 1N HCl(10ml), to the reflux mixture overnight.Concentrating under reduced pressure reaction mixture then, and with the acetone development, obtain the required product (107mg) of good purity.
XI. synthetic (7-two phosphono methylols)-2-methyl-2-pyridine iodide
Use and embodiment 3, the described basic identical method of part II changes into (7-two phosphono methylols)-2-methyl-2-pyridine iodide with [1-hydroxyl-(dihydro-2-pyridine-7-yl) methylene radical] two [phosphonic acids].
Embodiment 16
Synthetic 3-(2,2-two phosphono ethyls)-N, N, N-trimethylammonium-puratized agricultural spray oxyhydroxide, inner salt
Figure 931082781_IMG32
By following synthetic and preparation 3-(2,2-two phosphono ethyls)-phenyl-leptodactyline.
I. Synthetic 2-[3-nitrophenyl ethylidene] two [phosphonic acids] tetra-ethyl ester
In flask at the bottom of the dry 50ml garden of crossing of flame, under nitrogen environment, add and at first use the washed 1.12g potassium hydride KH of pentane (35% in oil, 10.59mmol).Add dry toluene (10ml), cooling suspension to 0 ℃.(3.31g 9.63mmol) finishes after the liquid feeding, at room temperature stirs 1 hour to be added dropwise to Tetraethyl diphosphonomethane.(2.09g 9.63mmol) is dissolved in the toluene of 10ml, to wherein adding anion solutions, at room temperature stirs and spends the night with 3-nitrobenzyl bromine in the flask of a 100ml.With this reaction mixture of diatomite filtration.Concentrating under reduced pressure then.By the thick slag of preparation property liquid-phase chromatographic analysis purifying, obtain 2-[3-nitrophenyl ethylidene] two [phosphonic acids] tetra-ethyl ester.
II. Synthetic 2-[3-aminophenyl ethylidene] two [phosphonic acids] tetra-ethyl ester
With 2-[3-nitrophenyl ethylidene] two [phosphonic acids] tetra-ethyl ester is dissolved in the ethanol (50ml), to wherein adding 10% palladium on carbon (Palladium on carbon(0.50g).Pressurization (40psi) jolting reaction mixture is 2 hours in a Pa Er hydrogenation bottle, takes in until hydrogen and finishes.Use the diatomite filtration reaction mixture.With fresh washing with alcohol diatomite, filter then, merge the washing with alcohol thing, and concentrating under reduced pressure.Residue is dissolved in the chloroform, separates amino adducts by extracting among the 6N 1 with its 1 salt form then.The waterbearing stratum reflux 12 hours that under nitrogen environment, will contain the amino adducts of tetra-ethyl ester form.Reaction mixture is used charcoal treatment, uses diatomite filtration then.The concentrating under reduced pressure filtered liquid obtains di 2 ethylhexyl phosphonic acid.
III. synthetic 3-(2,2-two phosphono hydroxyethyls)-phenyl-leptodactyline.
With 2-[3-aminophenyl ethylidene] in two [phosphonic acids] water-soluble (10ml) and the ethanol (2ml).Add excessive methyl iodide, backflow reacting by heating mixture is 48 hours under nitrogen environment.Reaction mixture, and concentrating under reduced pressure, the thick residue of recrystallize from water and ethanol obtains white solid puratized agricultural spray salt.
Embodiment 17
The Schenk model
Estimate in known animal model system such as the Schenk model in the bone metabolism field that bone resorption suppresses and the mineralising restraining effect in the body of this compound.The rule of this model system is described in people such as Shinoda, Calcif.Tissue Int., and 35,87-99(1983); With people Calcif Tissue Res.11 such as Schenk, 196-214(1973), all these are described by with reference to being combined in herein.
Material and method:
Animal
Male Sprague Dawley mouse (Charles River Breeding Laboratories) and its mother in 17 day age (30gm) of weaning are in advance transported together, after the arrival they are placed plastics cage together.During 19 day age, optionally give young mouse feeding thing and water, they are divided into treatment group and control group at random, every group of 7 animals.At the 1st day and the 7th day, all animal intraperitoneal (" IP ") injection fluorexon (was dissolved in 1% solution in 0.9% salts solution; Using dosage is the 0.2ml/100g body weight).(be dissolved in 1% solution in 0.9% salts solution for all animal peritoneal injection tetracycline hydrochloride at the 4th day; Using dosage 0.2ml/100g body weight).These compounds can activity mark's mineralising bone and cartilage.
Dosage solution and medication
All solution are made and are dissolved in 0.9% generic physiological brinish subcutaneous injection liquid, and transfer pH to 7.4 with NaOH and/or HCl.With with the corresponding mg/kg(body weight of mg phosphorus/kg) powder (according to molecular weight, the hydrate) weight of active substance of expression calculates solution dosage.Dosage according to the 0.2ml/100g body weight is determined concentration.Generally, all compounds are with 0.01,0.1, and 1.0 and 10.0mg phosphorus/kg/ days administration 7 days.When 0.1mg phosphorus/kg/ days dosage, show active compound, under logarithm reduces, test to 0.001mg phosphorus/kg/ days again.Adjust dosage according to the variation of body weight every day.
Ptomatopsia, organized processing and techtology
After the administration 8 days.Excessively the peritoneal injection Sodital is put to death all animals.The anatomical isolation shin bone, and place 70% ethanol.In the gradient ethanolic soln, make a shin bone dehydration, and be put in the methyl methacrylate, as described in Schenk, see Methods of Calcified Tissue Preparation(G.R.Dickson, Editor; Elsevier Science Publ., The Netherlands; 1984), the full content of its description is logical with reference to being incorporated into this paper.Pass dried epiphysis district and vertically cut shin bone.With the one side of cma staining sample, place on the microscopical slide glass, with a kind of Quantimet Image Analyzer(Cambridge Instruments, Inc.) estimate with incandescent light and UV-light.Dried epiphysis bone between mensuration fluorescent mark and the growth plate in the zone dyes content for a short time: represent with the per-cent that accounts for the total area (bone+marrow).The mean value of the measured value of 10 equidistant sections is decided to be the width of epiphyseal growth plate.
The parameter of use variable and distribution free analysis and Wilcoxons order number and check are carried out statistical analysis to determine the remarkable meaning of data statistics with respect to control group.This Schenk model provides this chemical combination object in-seam to absorb inhibiting data.
Embodiment 18
The adjuvant arthritis model
A variety of sacroiliitis animal models are arranged, and wherein having a kind of is the adjuvant-induced arthritis that utilizes mycobacterium butyricum (Mycobacterium butyricum).This model can be simulated the rheumatoid arthritis (arthroncus relevant with the pannus infringement with the joint cavity cell, bone resorption, CF and the release of lysosome composition in joint cavity) (1.2) of human body aspect some.A series of preventions and therapeutics studies show that anti-inflammatory drug (3.4) and di 2 ethylhexyl phosphonic acid compound have potential use value in Guan Guanyan treatment (5.6).
Reference
1.Pearson，C.，Wood F.（1959），Studies of Polyarthritis and Other Lesions Induced by Injection of Mycobacterial Adjuvant.I.General Clinical and Pathological Characteristics and Some Modifying Factors，Arth.Rheum.，2：440-459.
2.Blackman，A.，Burns，J.W.，Framer，J.B.，Radziwonik，H.，Westwick，J.（1977），An X-ray Analysis of Adjuvant Arthritis in the Rat.The Effect of Prednisolone and Indomethacin，Aqents and Actions，7：145-151.
3.Winter，C.A.，Nuss，G.W.（1966），Treatment of Adjuvant Arthritis in Rats with Anti-inflammatory Drugs，Arth.Rheum.，9：394-404.
4.Winder，C.V.，Lembke，L.A.，Stephens，M.D.（1969），Comparative Bioassay of Drugs in Adjuvant-Induced Arthritis in Rats：Flufenamic Acid，Mefenamic Acid，and Phenylbutazone，Arth.Rheum.，12：472-482.
5.Francis，M.D.，Flora，L.King，W.R.（1972），The Effects of Disodium Ethane-l-Hydroxy-l-Diphosphonate on Adjuvant Induced Arthritis in Rats，Calcif.Tiss.Res.，9：109-121.
6.Flora，L.（1979），Comparative Antiinflammatory and Bone Protective Effects of Two Diphosphonates in Adjuvant Arthritis，Arth.Rheum，22：340-346.
The adjuvant joint is a kind of serious honeycomb inflammation and synovitis of being brought out for male mouse (Sprague Dawley or Lewiws strain) subcutaneous (SC) Mycobacterium butyricum (Mycobacterium batyricum) mineral fluid of injection (8mg/ml) at the 0th day.Be administered once this compound of dosage of every day oral (PO) or non-enteron aisle (SC), and can measure by prevention (from the 0th day) or treatment (from the 9th day or 10 or 14 days) scheme.Compare the long-pending minimizing of corpus unguis by the sacroiliitis control group with the physiological saline treatment, lose weight, bone minimizing or reactive bone forming are newly measured and are suppressed sacroiliitis efficient.Stopped treatment checks that " outburst " react (inflammation overrun increase), and this reaction has represented that this compound keeps the ability of arthritis efficient.
Material and method
A. animal
The animal of using is a male Lewis mouse (LEW).After the arrival, number the mouse random packet by computer random, and the single cage that places iron wire to hang.Random feeding and water in whole research process.These animals are looked after and raised to regulation routine according to state and government.Each mouse before cage and mouse tail label for identification.
B. experimental design
Measured body weight (BW) and the rear solid end volume [(PV) use is write down by the mercury displacement method with computer banded pressure transmitter] of all mouse at the 1st day.At the 0th day with MFA[4.4mg/kg mycobacterium butyricum (Mb) oil] by the following sacroiliitis of bringing out: anesthetized mice, and under aseptic condition in MFA of root of the tail portion subcutaneous injection.
Long-pending and the body weight of corpus unguis usually biweekly, is measured in after this processing several days.Concerning a little prevention scheme, mouse is divided into the group that is made up of 8-10 mouse at random, treatment continued the straight end of treatment every day since the 0th day.For treatment plan, mouse was divided at random the treatment group of forming by 8-10 mouse according to its PV at the 10th day.Began to give dose drug on the 10th day until just testing eventually.Concerning two kinds of schemes, the 10th day or before animal is placed the footwear box cage that has thick-layer pad grass.
Formulation solution
Be applicable to the medicine that is difficult for oxidation
Weigh the thing of getting it filled in the balance, in the flask of containing mark is arranged, mix then with distilled water.Transfer the pH to 7.4 of this solution with 0.1N NaOH.Pass through this solution of sterilization filter paper filtering of one 0.45 μ m then in a kind of sterilization storage vessel.When not making, solution is deposited in the refrigerator.
Be applicable to the medicine of easy oxidation
Weigh the thing of getting it filled in the balance, have in the flask of containing mark one then and mix with the water that removes oxygen.Aseptic filter paper by one 0.45 μ m is filled into stoste in the molten device of a kind of aseptic storage, when not using, stoste is left in the refrigerator.
According to the situation of every day, from stoste, take out the solution of specified quantitative, in the capacity beaker of packing into little, transfer to pH7.4 according to predetermined calculated value then.Can also the solution of regulating further be diluted (with the water that removes oxygen) if desired.
Purity, mg/kg(body weight according to molecular weight, compound) consumption and final required mg P/kg concentration medicine is calculated.The dose unit of each mouse is the 0.1ml/100gm body weight, in film thigh ditch pleat place's subcutaneous injection of animal, or the 1ml/200gm body weight, uses a kind of stainless steel delivery tube oral administration of bending.Adjust dosage according to body weight change weekly.
Irradiation film making, ptomatopsia and collection tissue
Administration is used 1ml Socomb after stopping
Figure 931082781_IMG33
Every mouse is put to death in intraperitoneal (IP) administration.Immediately with Torrox 120 D X-line units in MA=5, give the non-photography of whole mouse body and function Kodak with the film making of medical science film under the condition of ISUP=50 and time=60 second.Take off hind leg from every mouse, and, carry out fixing equally to a slice liver,kidney,spleen and thimus tissue simultaneously with 10% buffered formalin fixed.Use 4%EDTA, PH 7.4 makes the articulatio tibiotarsalis decalcification, conventional processing in paraffin mass, and carry out H+E dyeing.The organ part is also handled with paraffin mass and H+E dyeing.
Use opticmicroscope Histological section to be carried out the qualitative evaluation of the degree of impairment of its bone and soft tissue.All four limbs are radiated take pictures, with the subjectivity marking standard of 0-60 the bone resorption (BR) of 4 positions of 6 anatomy trabecular bone positions of each hind leg and each forelimb is carried out classification according to the 0-3 level.For the new bone forming of reactivity (RNB), by the severity of 0-3 classification is carried out in the outside of shin bone and the radiograph on medical treatment surface, and the classification of 0-2 level is pressed in above-mentioned every other zone, press the subjective marking of 0-44.
D. statistical analysis
With Stadent ' s T-check and with Tukey carry out that univariate analysis (SAS) (12) is long-pending to corpus unguis, bone resorption and reactive new osteoplastic data analyze.P=0.05 or think to have the significance of difference more for a short time.
This model is compared with the sacroiliitis animal of physiological saline treatment provides effect data in the body of arthritis compound aspect reducing loss of pawl swelling bone and reactive new bone forming.
Embodiment 19
Preparation has the capsule of following component:
Each capsule of active ingredient mg/
3-(2,2-two phosphono ethyls)-1-350.0
(2-mercaptoethyl) pyridinium chloride
Vehicle
Lactose 90.0
Microcrystalline Cellulose 60.0
Magnesium Stearate 1.0
The capsule that has above-mentioned component by following conventional process preparation:
Active ingredient was mixed about 10 minutes in shell rotation mixer with Microcrystalline Cellulose.
With 80 hole sizers of gained mixture by a sledge mill.
Mixture was placed two overcoat mixing tank remix about 15 minutes again with lactose.
Add Magnesium Stearate then, remix 5 minutes.On the capsule filling machine that a piston promotes, the compression of gained mixture is incapsulated.
Can substitute the active ingredient in the capsule of above-mentioned preparation according to any compound of embodiment 1 to 13 and embodiment 15 preparations.
Embodiment 20
Preparation has the tablet of following component:
Each capsule of active ingredient mg/
3-(2-hydroxyl-2,2-two phosphono ethyls) 700.0
-1-(methyl) pyridine iodide disodium salt
Vehicle
Lactose (spray-dired) 200.0
Starch (1500) 100.0
Magnesium Stearate 25.0
Be prepared as follows tablet with habitual method with above-mentioned component:
Active ingredient was ground in ball milling about 30 minutes.The active ingredient that will grind mixed in the twayblade mixing tank about 20 minutes with spray-dired lactose then.
In mixture, add starch, and then mixed 15 minutes.On the standard tabletting machine with the mixture tablet forming.
Can substitute active ingredient in the above-mentioned preparation tablet according to any compound of embodiment 1 to 13 and embodiment 15 preparations.
Embodiment 21
Use the normal saline solution of 10.0ml and the 3-(2-hydroxyl-2 of 7.0mg phosphorus, 2-two phosphono ethyls)-1-picoline hydroxyl inner salt, transfer pH=7.4.
Injected once every day totally 4 days, and can alleviate the hypercalcinemia of the about 70 kilograms malignant tumor patient of body weight satisfactorily.
Can replace the active ingredient in the injection liquid of above-mentioned preparation according to any compound of embodiment 1-16 preparation.
Embodiment 22
Be representative dentifrice composition of the present invention below.
Component wt%
3-(3,3-two phosphono propyl group)-1-2.0
The cetyl pyridinium disodium salt
Sorbyl alcohol 33.0
Asccharin 0.46
Silicon-dioxide 22
NaF 0.243
Glycerine 9
NaOH(50% solution) 0.2
Carboxyvinyl polymer (Carbopol) 0.2
Keltrol 0.6
TiO 20.5
Sodium alkyl sulfate (28% solution) 4
PEG 6 3
FD ﹠amp; C Blue # 1(1% solution) 0.05
Seasonings 1.1
The water capacity
At first, mechanically mixing TiO 2, silicon-dioxide, carboxyvinyl polymer and X-glue (Keltrol).These all are solids.Set aside.Second step, active ingredient (2% di 2 ethylhexyl phosphonic acid pyridine) is water-soluble, and transfer to about pH=7.Then with NaF, sorbyl alcohol, asccharin, glycerine, PEG 6 and F ﹠amp; DC Blue#1(1% solution) be dissolved in and contain in the water mixed liquid.Add sodium alkyl sulfate (28% solution) then in mixed solution, NaOH is at last with seasonings.Add solid mixture at last, guarantee paste fully and thorough mixing (temperature is no more than 150F) and carboxyvinyl polymer and X-peptization separate.Check the last pH in this stage, and transfer to Ph=7.0 if desired.(by 1: 4 said dentifrice agent slurries rotation is added in the entry, the pH that measures supernatant liquor finishes the inspection of pH).
Embodiment 23
Be that the representational collutory component of the present invention is given an example below:
Component wt%
3-(3,3-two phosphono propyl group)-1-0.1
The cetyl pyridinium disodium salt
EtOH（200 proof） 16.25
Tensio-active agent (tween 80) 0.12
Glycerine 10
Asccharin 0.06
Seasonings 0.041
F ﹠amp; DC Blue #1(1% solution) 0.022
F ﹠amp; DC Yellow #5(1% solution) 0.018
Phenylformic acid 0.0045
Sodium Benzoate 0.054
Water is an amount of
At first, active ingredient (as 0.5%) is water-soluble, transfer to PH=7 with NaOH if desired.Add EtoH then, glycerine, asccharin, F ﹠amp; DC Blue #1, F ﹠amp; DC Yellow #5, phenylformic acid and Sodium Benzoate.Seasonings is dissolved in the tensio-active agent, and these mixtures join in the above-mentioned composition.Check PH, if desired, regulate PH.
Embodiment 24
A Caucasian, the male sex, about 92 kilograms of body weight, 72 years old age, suffer from the moderate even serious right side lacquer arthralgia, the time swelling arranged.After malaise symptoms increased to about 1 year, he went to see the doctor, and diagnosis is an osteoarthritic right knee joint, and the X-radiodiagnosis x further is confirmed.
After the property improved pain killer (NSAIDS) treatment after a while (comprising Asprin, naproxen, Ketoprofen), his symptom continues to worsen some decline of physical appearance.He goes back again to see the doctor, and the doctor allows it use the prepared tablet of embodiment 20, and every day twice, ante cibum or two hours are after meal taken three months courses of treatment.After the trimestral treatment, pain and swelling clinical symptom are significantly improved, the lengthening of especially walking.At trimestral treatment end, dosage is 2 slices/day, and continuation uses half of the described dosage that begins to write out a prescription to measure (also being 1 slice/day) aperiodically.
Embodiment 25
Women Black people, about 65 kilograms of body weight, 55 years old age, the articulations digitorum manus swelling and the distortion of present two hands, the part ability of hand and finger and/or skill forfeiture.According to several suitable Clinical Laboratory that naked eyes and X-ray examination and American Rheumatism Association are admitted, make a definite diagnosis her and suffer from rheumatoid arthritis.
After unsuccessful pain relieving and anti-inflammatory therapy, her physician has opened among the embodiment 20 tablet of preparation to her, every day secondary, ante cibum or two hours are after meal taken medicine 4 months courses of treatment.After one month the treatment, dactylus swelling symptom is obviously improved, and the finger scope of activity significantly increases; She has continued to finish four months the course of treatment, and her doctor continues to have opened bimestrial medicine to her afterwards.
Embodiment 26
A women Spaniard, at 12 years old age, about 37 kilograms of body weight is because of spontaneous juvenile rheumatoid arthritis is sought medical advice.Symptom shows as multi-joint inflammation significantly, with heating and tenderness, shows that the quick and pathologic of function of joint is degenerated.
Her physician recommends her to go to see a rheumatosis expert, and this expert gives her with the property strengthened treatment at once, gives the solution of her intravenous injection embodiment 21 described preparations in three days time, and injection speed is injected 1 time every day, administration two hours.When intravenous injection finished, the doctor had opened the prepared tablet of embodiment 20 to her, continues treatment two months, in therapeutic process, obviously improve, and movable increasing, pain subtracts.In following two middle of the month, the doctor reduces to 3 of 3/4, two day of original oral dosage clothes with its dosage, also promptly one day 2 with 1 day 1 be used alternatingly.Reduce to dosage 1/4 of former dosage when finishing this course of treatment again, gives the capsule of preparation among the embodiment 19, and every day 1, capsules was obeyed 4 months again.
Embodiment 27
A Caucasia male patient of 17 years old went to see that the odontologist carried out routine examination for the first time in 5 years.Visual inspection patient's oral cavity finds, the lingual surface of lower incisor and on grind one's teeth in sleep far away in the surface dental plaque and dental calculus formation are arranged.Attempt to remove the accumulation of dental plaque and dental calculus and do not succeed by the mechanical removal method.The 3-(3 that the doctor allows the patient use the embodiment 23 of 0.1% weight ratio of 15ml to prepare, 3-two phosphonos propyl group-1-cetyl pyridinium, the oral cavity solution of disodium salt was gargled 1 minute, and dental plaque and dental calculus promptly are easy to remove with mechanical means painlessly.The odontologist comprises course of treatment of wanting him to carry out a kind of prevention with the said prevention of brushing teeth of the dentifrice agent of the above-claimed cpd of embodiment 22 preparations and comprises with said dentifrice agent the course of treatment and to brush teeth 3 totally months one time three minutes every day then.During three the end of month, patient's dental plaque and tartar problem are controlled.This patient can use general toothpaste, and his odontologist comprises the 3-(3 with 0.1%, 3-two phosphono propyl group to the Concept of Maintenance that he has formulated a tartar, antiplaque)-1-cetyl pyridinium disodium salt solution rinses the mouth once every day.
Embodiment 28
A Black people married woman of 60 years old suffers from the painful gingivitis, goes to see for the first time the odontologist in 10 years.Her oral cavity of visual inspection finds along the gum line serious dental plaque and tartar are arranged.Attempt to remove dental plaque and tartar by mechanical means, disease goes into to be difficult to bear the pain.The odontologist allows patient with the 3-(3 of 0.1% weight ratio of 10ml, 3-two phosphono propyl group)-the 1-cetyl pyridinium, disodium salt solution is rinsed the mouth three times, each one minute, promptly is easy to remove dental plaque and dental calculus with general mechanical means.Odontologist's prescription is then: with a kind of 3-(3 that contains 2.0% weight ratio, and 3-two phosphono propyl group)-the 1-cetyl pyridinium, every day brushed teeth twice by the dentifrice agent of disodium salt, each one minute.Said scheme continues 6 months.Patient is the odontologist once more, and her dental plaque and tartar problem are under control, and gingivitis also is improved.The odontologist has formulated and has consolidated scheme, uses the 3-(3 of 0.1% weight ratio of 10ml, 3-two phosphono propyl group)-the 1-cetyl pyridinium, disodium salt solution is rinsed the mouth once every day.Said scheme continues 6 months.Patient goes to see the odontologist once more; Her dental plaque and tartar problem are controlled, and gingivitis is improved.The odontologist has formulated and has consolidated scheme; 0.1% 3-(3 with 10ml; 3-two phosphono propyl group)-the 1-cetyl pyridinium; disodium salt solution is rinsed the mouth once every day; and with the 3-(3 that contains 2% weight ratio; 3-two phosphono propyl group)-and the 1-cetyl pyridinium, the toothpaste of disodium salt is brushed teeth once every day.
Embodiment 29
A Caucasia women of 60 years old, body weight 62kg suffers from serious backache.Her physician is under radiologist's assistance, and being diagnosed as her may suffer from L1 vertebra crushing property fracture because of the osteoporotic bone resorption.To patient's system the treatment plan of three months courses of treatment, dosage is the tablet by embodiment 20 described preparations of 700mg once a day.Before having a dinner two hours or with the capsule of taking 700mg after the meal in two hours at every turn.After three months, dosage reduces to a 350mg capsule by embodiment 19 preparations, every one day clothes once; Three months courses of treatment.Her physician uses maintenance dose to her then, takes a 100mg capsule by embodiment 19 described method preparations every day, six months courses of treatment.After six months, this disease is again without any backache.X-ray examination shows not fracture in addition subsequently.
Embodiment 30
An east women of 75 years old, Hip Fracture takes place because of falling down the back in 53 kilograms of body weight.Be diagnosed as after she is in hospital and suffer from osteoporosis.The treatment plan of formulating is the injection thyrocalcitonin.Because injection thyrocalcitonin pain very concerning patient, the patient can not cooperate said calcitonin treatment.Take 700mg tablet to her, every day twice, obeyed one month by embodiment 20 described preparations.When one month treatment finishes, change 1 time 700mg tablet clothes every day again, continue and obeyed two months.After finishing two months the course of treatment, she obeys the 100mg capsule by embodiment 19 described preparations again, one of every day, obeys three months.When seeing the doctor afterwards, determine that by determination of light absorption the mineralising density of its forearm does not obviously descend.
Embodiment 31
An American of 85 years old, the male sex, 65 kilograms of body weight are because of the doctor that sees a physician is gone in serious backache.X-ray examination is found to cause the slight vertebral body damage in many places because of the obvious bone loss that osteoporosis causes.Formulated bimestrial treatment plan to patient, obeyed a slice 700mg tablet and a 350mg capsule every day, be separated by 8 hours, tablet and capsule are pressed embodiment 20 and 19 described method preparations respectively.By after this scheme two months, dosage reduced to obey a 350mg capsule every day, obeyed two months.X-ray examination is found another place crushing property fracture then.Take the 100mg capsule of maintenance dose again to him, once a day, obeyed 6 months.After six months, do not find that tangible bone density reduces.

Claims (42)

1, a kind of phosphinic acid compounds and its pharmacy acceptable salt and ester that contains quaternary nitrogen has following structure:
Wherein m and n are 0 to 10 integers; M+n is from 0 to 10;
(a) Q is that a covalent linkage or one are selected from O, S, NR 1Group;
(b) Y is N +(R 8) 2Or C (R 1) 2With working as Y is C (R 1) 2The time, at least one R 2Must be N +(R 8) 3
(c) Z be one saturated, undersaturated or aromatic, monocycle or encircle carbocyclic ring, or contain one or more O of being selected from, the heteroatomic monocycle of S or N or encircle heterocycle more more;
(d) R is PO 3H 2Or (OH) R of P (O) 4, R wherein 4It is alkyl that replace or a unsubstituted 1-8 carbon atom;
(e) each R 1Be to be selected from following one group: zero; SR 6R 9SR 5-O 2CR 3Hydrogen; Hydroxyl; Replace or unsubstituted C 1-C 8Alkyl;-OR 3-CO 2R 3-O 2CR 3-NR 3 2-N (R 3) C (O) R 3-C (O) N (R 3) 2Halogen;-C (O) R 3Arylalkyl; Nitro; Replace or unsubstituted aryl, and their combination;
(f) each R 2Be the one or more substituting groups on the Z group, be independently selected from following one group: N +(R 8) 3SR 6R 9SR 6Hydrogen; That replace or unsubstituted C 1-C 8Alkyl; OR 3-CO 2R 3-O 2CR 3-NR 3 2-N (R 3) C (O) R 3-C (O) N (R 3) 2Halogen; Hydroxyl;-C (O) R 3Arylalkyl; Nitro; Replace or unsubstituted aryl;
(g) each R 3Be to be independently selected from following one group: hydrogen, replace or the unsubstituted alkyl that contains 1-8 carbon atom, and R 9SR 6
(h) R 5Be to be selected from following one group: hydrogen; Halogen; SR 6R 9SR 6Amino; Hydroxyl; With replacement or unsubstituted C 1-C 8Alkyl;
(i) each R 6Be independently selected from following one group: H;-C (O) R 7-C (S) R 7-C (O) NR 7 2-C (S) N (R 7) 2-C (S) OR 7-C (O) OR 7R wherein 7Be hydrogen or replacement or unsubstituted C 1-C 8Alkyl.
(j) each R 8Be independently selected from following one group: zero, replace or unsubstituted alkyl with 1-35 carbon atom, replace or unsubstituted phenyl benzyl, or R 9SR 6With
(k) R 9Be a replacement or unsubstituted C 1-C 8Alkyl;
2, a kind of phosphinic acid compounds that contains quaternary nitrogen according to claim 1, wherein Z is that a monocyclic heterocycles group and Y are N +(R s) 2
3, a kind of compound according to claim 2, wherein Z is a hexa-member heterocycle.
4, a kind of compound according to claim 3, wherein Z is a pyridine, pyrimidine, and piperidines.
5, a kind of compound according to claim 4, wherein Z is a pyridine.
6, a kind of compound according to claim 2, wherein Z is 5 yuan of heterocycles.
7, a kind of compound according to claim 6, wherein Z is an imidazoles, thiazole ， oxazole, pyrroles (pyrrlium) or tetramethyleneimine.
8, a kind of compound according to claim 1, wherein Z is the heterocyclic group of ring more than.
9, a kind of compound according to Claim 8, wherein Z is one and a five-ring condensed six-ring.
10, a kind of compound according to claim 9, wherein Z is an indoles (indoliam), imidazoles-(1,2-a) pyridine and pyridine.
11, a kind of compound according to claim 10, wherein Z is one and six-ring condensed six former subrings.
12, a kind of compound according to claim 1 I, wherein Z is a quinoline, isoquinoline 99.9, tetrahydroquinoline and octahydro quinoline.
13, a kind of compound according to claim 1, wherein Q is N or NR 1
14, a kind of compound, wherein R according to claim 1 1Be to be independently selected from-SR 5; R 9SR 6; Hydrogen; Replace or unsubstituted C 1-C 8Alkyl;-NR 32; Or-CO 2R 3
15, a kind of compound, wherein R according to claim 14 1Be-SR 6; R 9SR 6; Or hydrogen.
16, a kind of compound, wherein R according to claim 1 2Be to be selected from-SR 6; R 9SR 6; Hydrogen; Replace or unsubstituted C 1-C 8Alkyl;-NR 32; OR 3; Or-CO 2R 3
17, a kind of compound, wherein R according to claim 16 2Be-SR 6; R 9SR 6; Or hydrogen.
18, a kind of compound, wherein R according to claim 1 3Be hydrogen; R 9SR 6; Or C unsubstituted or that replace 1-C 8Alkyl.
19, a kind of compound, wherein R according to claim 14 3Be hydrogen; Or R 9SR 6
20, a kind of compound, wherein R according to claim 18 3Be hydrogen or R 9SR 6
21, a kind of compound, wherein R according to claim 14 6Be H ,-C(O) R 7; C(S) R 7; Or C(O) N(R 7) 2
22, a kind of compound, wherein R according to claim 21 6Be H ,-C(O) R 7; Or C(S) R 7
23, a kind of compound, wherein R according to claim 19 6Be H ,-C(O) R 7; C(S) R 7; Or C(O) N(R 7) 2
24, a kind of compound, wherein R according to claim 21 6Be H ,-C(O) R 7; C(S) R 7; Or C(O) N(R 7) 2
25, a kind of compound, wherein R according to claim 16 6Be H ,-C(O) R 7; C(S) R 7; Or C(O) N(R 7) 2
26, a kind of compound according to claim 1, wherein Z is a monocycle carbon ring group; Y is C(R 1) 2With at least one R 2Be N +(R 8) 3
27, a kind of compound according to claim 1, wherein Z is the carbon ring group of ring more than; Y is C(R 1) 2With at least one R 2Be N +(R 8) 3
28, a kind of pharmaceutical composition, contain:
(a) a kind of safety and significant quantity contains the quaternary nitrogen heterocycles phosphinic acid compounds according to claim 1;
(b) a kind of medicinal vehicle.
29, a kind of pharmaceutical composition, contain:
(a) a kind of safety and significant quantity contains the quaternary nitrogen heterocycles phosphinic acid compounds according to claim 2; With
(b) a kind of medicinal carrier.
30, a kind of pharmaceutical composition, contain:
(a) a kind of safety and significant quantity contains the quaternary nitrogen heterocycles phosphinic acid compounds according to claim 6; With
(b) a kind of medicinal vehicle.
31, a kind of pharmaceutical composition, contain:
(a) a kind of safety and significant quantity contains quaternary nitrogen carbocyclic ring phosphinic acid compounds according to claim 26; With
(b) a kind of medicinal vehicle.
32, a kind of pharmaceutical composition, contain:
(a) a kind of safety and significant quantity contains quaternary nitrogen carbocyclic ring phosphinic acid compounds according to claim 27; With
(b) a kind of medicinal vehicle.
33, be used for the treatment of or prevent abnormal calcium and phosphate metabolism disease contain quaternary nitrogen phosphonic acids and pharmacy acceptable salt and ester, it is characterized in that they have general formula:
Figure 931082781_IMG3
Wherein m and n are 0 to 10 integers; M+n is from 0 to 10;
(a) Q is that a covalent linkage or one are selected from O, S, NR 1Group;
(b) Y is N +(R s) 2Or C(R 1) 2And when Y be C(R 1) 2The time, at least one R 2Must be N +(R 8) 3;
(C) Z be one saturated, undersaturated, or fragrance, monocycle or encircle carbocyclic ring, or a monocycle or encircle heterocycle more more, this heterocycle contains one or more O of being selected from, the heteroatoms of S or N, a preferred monocyclic heterocycles or monocycle carbocyclic ring;
(d) R is PO 3H 2; Or P(O) (OH) R 4, R wherein 4Be alkyl that replace or a unsubstituted 1-8 carbon atom, preferred PO 3H 2;
(e) each R 1Be to be selected from following one group: zero; SR 6; R 9SR 6; Hydrogen; Hydroxyl; Replace or unsubstituted C 1-C 8Alkyl;-OR 3;-CO 2R 3; O 2CR 3;-NR 32;-N(R 3) C(O) R 3;-C(O) N(R 3) 2; Halogen;-C(O) R 3; Arylalkyl; Nitro; Replace or unsubstituted aryl, and their combination; Preferred SR 6, R 9SR 6, hydrogen, the C of replacement 1-C 8Alkyl ,-NR 32 or CO 2R 3;
(f) each R 2Be the one or more substituting groups on the Z group, be independently selected from following one group: N +(R 8) 3; SR 8; R 9SR 6; Hydrogen; That replace or unsubstituted C 1-C 8Alkyl; OR 3;-CO 2R 3;-O 2CR 3;-NR 32;-N(R 3) C(O) R 3;-C(O) N(R 3) 2; Halogen; Hydroxyl;-C(O) R 3; Arylalkyl; Nitro; Replace or unsubstituted aryl; Preferred N +(R 8) 3; SR 8; R 9SR 6; Hydrogen; That replace or unsubstituted C 1-C 8Alkyl;-NR 32; OR 3;-CO 2R 3
(g) each R 3Be to be independently selected from following one group: hydrogen, replace or the unsubstituted alkyl that contains 1-8 carbon atom, and R 9SR 6; Preferred hydrogen, R 9SR 6Or replacement or unsubstituted C 1-C 8Alkyl;
(h) R 5Be to be selected from following one group: hydrogen; Halogen; SR 6; R 9SR 6; Amino; Hydroxyl; With replacement or unsubstituted C 1-C 8Alkyl; Preferred hydrogen, SR 6; R 9SR 6;
(i) each R 6Be independently selected from following one group: H;-C(O) R 7;-C(S) R 7;-C(O) NR 72;-C(S) N(R 7) 2;-C(S) OR 7;-C(O) OR 7; R wherein 7Be hydrogen or replacement or unsubstituted C 1-C 8Alkyl, preferred hydrogen ,-C(O) R 7;-C(S) R 7;
(j) each R 8Be independently selected from following one group: zero, replace or unsubstituted alkyl with 1-35 carbon atom, replace or unsubstituted phenyl benzyl, or R 9SR 8; The preferred replacement or unsubstituted alkyl with 1-35 carbon atom;
(k) R 9Be a replacement or unsubstituted C 1-C 8Alkyl;
34, a kind of heterocycle phosphinic acid compounds that contains quaternary nitrogen according to claim 1, wherein Z is that a monocyclic heterocycles group and Y are N +(R 8) 2
35, a kind of wherein Z is a hexa-member heterocycle according to any one compound of aforementioned claim, preferred pyridine, pyrimidine, and piperidines.
36, a kind of wherein Z is a five-membered ring according to any one compound of aforementioned claim, preferred imidazoles, thiazole ， oxazole, pyrroles or tetramethyleneimine.
37, a kind of compound according to claim 1, wherein Z is the heterocyclic group of ring more than, preferably one and a five-ring condensed six-ring, indoles (indolium) more preferably, imidazoles-(1,2-a) pyridine, and pyrindine (pyrindinium).
38, a kind of compound according to claim 1, wherein Z is one and six-ring condensed six-ring, preferred quinoline, isoquinoline 99.9, tetrahydroquinoline and octahydro quinoline azoles.
39, a kind of compound according to claim 1, wherein Z is a monocycle carbon ring group; Y is C(R 1) 2, and at least one R 2Be N +(R 8) 3
40, a kind of compound according to claim 1, wherein Z is the carbon ring group of ring more than; Y is C(R 1) 2And at least one R 2Be N +(R 8) 3
41, a kind of pharmaceutical composition of thanking to relevant disease with abnormal calcium and phosphatization that is used for the treatment of is characterized in that it contains:
(a) a kind of safety and significant quantity according to aforementioned claim any one contain the quaternary nitrogen phosphinic acid compounds;
(b) a kind of medicinal vehicle.
42, the application of each compound in the preparation medicine among the claim 1-8, this medicine is to be used for the treatment of or pathological state that prevention is relevant with the phosphoric acid metabolism with abnormal calcium or human body or other mammiferous tartar, dental plaque and the gingivitis that is used for the treatment of and prevents this treatment of needs, it is characterized in that this application comprise to the aforementioned claim of said human body or other Mammalss one safe and effective amount each contain the quaternary nitrogen phosphinic acid compounds.
CN93108278A 1992-05-29 1993-05-29 Novel quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental Expired - Fee Related CN1042031C (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US89088592A 1992-05-29 1992-05-29
US890,885 1992-05-29
US052,695 1993-04-30
US08/052,695 US5391743A (en) 1992-05-29 1993-04-30 Quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental calculus and plaque

Publications (2)

Publication Number Publication Date
CN1088213A true CN1088213A (en) 1994-06-22
CN1042031C CN1042031C (en) 1999-02-10

Family

ID=26730954

Family Applications (1)

Application Number Title Priority Date Filing Date
CN93108278A Expired - Fee Related CN1042031C (en) 1992-05-29 1993-05-29 Novel quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental

Country Status (23)

Country Link
US (1) US5770586A (en)
EP (1) EP0646119B1 (en)
JP (1) JPH07506569A (en)
CN (1) CN1042031C (en)
AT (1) ATE168379T1 (en)
AU (1) AU662991B2 (en)
CA (1) CA2136825C (en)
CZ (1) CZ297094A3 (en)
DE (1) DE69319732T2 (en)
DK (1) DK0646119T3 (en)
ES (1) ES2118967T3 (en)
FI (1) FI945596A (en)
HK (1) HK1013075A1 (en)
HU (1) HUT72061A (en)
IL (1) IL105835A (en)
MX (1) MX9303243A (en)
NO (1) NO307055B1 (en)
NZ (1) NZ253541A (en)
PH (1) PH31246A (en)
PL (1) PL174761B1 (en)
RU (1) RU2126414C1 (en)
SK (1) SK144894A3 (en)
WO (1) WO1993024498A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110123662A (en) * 2019-04-30 2019-08-16 杭州伊瑟奇生物科技有限公司 Based on the gutta-percha for ionizing peeling effect and to the stripping means of oral bacteria and tartar

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL175046B1 (en) * 1992-05-29 1998-10-30 Procter & Gamble Pharma Novel thio-substituted heterocyclic phosphonate compounds containing nitrogen
US5451401A (en) * 1993-09-29 1995-09-19 The Procter & Gamble Company Diphosphonic acid esters as tartar control agents
US6555529B1 (en) 1997-12-25 2003-04-29 Toray Industries, Inc. Remedies for intramedullary diseases
DE60043648D1 (en) * 1999-07-19 2010-02-25 Toray Industries MEDICAMENTS FOR THE TREATMENT OF PERIODONTAL DISEASES
PL194770B1 (en) * 2001-03-19 2007-07-31 Adamed Sp Z Oo Method of obtaining risedronic acid
KR100638122B1 (en) * 2001-12-21 2006-10-24 더 프록터 앤드 갬블 캄파니 Method for the treatment of bone disorders
FR2838339B1 (en) * 2002-04-12 2005-06-24 Univ Angers POLYPHOSPHONATE DERIVATIVES FOR DENTIFRING COMPOSITIONS
US20040086581A1 (en) * 2002-11-06 2004-05-06 Jones Edwin B. Bio-energetic joint and arthritis pain formula
FR2959667B1 (en) * 2010-05-10 2016-01-01 Oreal COSMETIC COMPOSITION FOR MAKE-UP AND / OR CARE
IL279966A (en) * 2021-01-05 2022-08-01 O Y M Innovation Ltd Phosphonates and n-halamines compositions for tartar removal

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4208401A (en) * 1977-08-19 1980-06-17 Colgate-Palmolive Company Quaternary ammonium alkylene diphosphonate anti-calculus agents
DE2745083C2 (en) * 1977-10-07 1985-05-02 Henkel KGaA, 4000 Düsseldorf Hydroxydiphosphonic acids and processes for their preparation
DE3016289A1 (en) * 1980-04-28 1981-10-29 Henkel KGaA, 4000 Düsseldorf METHOD FOR PRODUCING OMEGA-AMINO-1-HYDROXYALKYLIDEN-1,1-BIS-PHOSPHONIC ACIDS
FR2531088B1 (en) * 1982-07-29 1987-08-28 Sanofi Sa ANTI-INFLAMMATORY PRODUCTS DERIVED FROM METHYLENEDIPHOSPHONIC ACID AND THEIR PREPARATION METHOD
FR2558837B1 (en) * 1984-01-26 1986-06-27 Sanofi Sa METHYLENEDIPHOSPHONIC ACID DERIVATIVES, PROCESS FOR OBTAINING SAME AND ANTIRHUMATISMAL DRUGS CONTAINING THEM
DE3428524A1 (en) * 1984-08-02 1986-02-13 Boehringer Mannheim Gmbh, 6800 Mannheim NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
US4687768A (en) * 1984-12-21 1987-08-18 The Procter & Gamble Company Certain hexahydroindan-2,2-diphosphonic acids useful in treating diseases associated with abnormal calcium and phosphate metabolism
US5104863A (en) * 1984-12-21 1992-04-14 The Procter & Gamble Company Certain bicycloalkane and azabicycloalkane-1,1-diphosphonic acid derivatives useful for treating diseases associated with abnormal calcium and phosphate metabolism
PH27078A (en) * 1984-12-21 1993-02-01 Procter & Gamble Pharmaceutical compositions containing geminal diphosphonates
IL77243A (en) * 1984-12-21 1996-11-14 Procter & Gamble Pharmaceutical compositions containing geminal diphosphonic acid compounds and certain such novel compounds
DE3776880D1 (en) * 1986-11-21 1992-04-02 Ciba Geigy Ag NEW SUBSTITUTED ALKANDIPHOSPHONIC ACIDS.
DE3640938A1 (en) * 1986-11-29 1988-06-01 Boehringer Mannheim Gmbh NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND
US5071840A (en) * 1986-12-19 1991-12-10 Norwich Eaton Pharmaceuticals, Inc. Certain heterocyclic substituted diphosphonate compounds pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism
US4868164A (en) * 1986-12-19 1989-09-19 Norwich Eaton Pharmaceuticals, Inc. Octahydro-pyridine diphosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
IL86951A (en) * 1987-07-06 1996-07-23 Procter & Gamble Pharma Methylene phosphonoalkyl-phosphinates and pharmaceutical compositions containing them
ATE90353T1 (en) * 1987-12-11 1993-06-15 Ciba Geigy Ag ARALIPHATYLAMINOALKANEDIPHONIC ACIDS.
GB8808138D0 (en) * 1988-04-07 1988-05-11 Leo Pharm Prod Ltd Chemical compounds
JPH01258695A (en) * 1988-04-07 1989-10-16 Yamanouchi Pharmaceut Co Ltd (pyrazolylamino)methylenebis(phosphinic acid) derivative and medicine thereof
US4933472A (en) * 1988-04-08 1990-06-12 Yamanouchi Pharmaceutical Co., Ltd. Substituted aminomethylenebis(phosphonic acid) derivatives
DE3822650A1 (en) * 1988-07-05 1990-02-01 Boehringer Mannheim Gmbh NEW DIPHOSPHONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
TW198039B (en) * 1988-11-28 1993-01-11 Ciba Geigy Ag
AU628158B2 (en) * 1989-04-03 1992-09-10 Upjohn Company, The Geminal bisphosphonic acids and derivatives as anti-arthritic agents
DE4011777A1 (en) * 1989-04-14 1990-10-18 Ciba Geigy Ag New tri:alkyl:ammonio 1-hydroxy-alkane-1,1-di:phosphonic acids - are calcium metabolism regulants e.g. for treating osteoporosis of calcium deposition in blood vessels
US4922007A (en) * 1989-06-09 1990-05-01 Merck & Co., Inc. Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
AU7165791A (en) * 1990-01-12 1991-08-05 Rhone-Poulenc Rorer International (Holdings) Inc. 1-azetidyl and 1-hexamethylenimine alkyl or aryl bisphosphonic acids and their use as pharmacological agents
PL175475B1 (en) * 1992-05-29 1999-01-29 Procter & Gamble Pharma Novel sulphur containing phosphonate compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110123662A (en) * 2019-04-30 2019-08-16 杭州伊瑟奇生物科技有限公司 Based on the gutta-percha for ionizing peeling effect and to the stripping means of oral bacteria and tartar

Also Published As

Publication number Publication date
EP0646119A1 (en) 1995-04-05
CA2136825C (en) 1997-10-28
NO944516D0 (en) 1994-11-25
NO307055B1 (en) 2000-01-31
CZ297094A3 (en) 1995-12-13
EP0646119B1 (en) 1998-07-15
IL105835A (en) 2000-08-13
ES2118967T3 (en) 1998-10-01
HU9403412D0 (en) 1995-02-28
US5770586A (en) 1998-06-23
AU4394593A (en) 1993-12-30
WO1993024498A1 (en) 1993-12-09
CA2136825A1 (en) 1993-12-09
CN1042031C (en) 1999-02-10
SK144894A3 (en) 1995-07-11
PL174761B1 (en) 1998-09-30
DK0646119T3 (en) 1998-12-14
RU94046106A (en) 1996-09-27
JPH07506569A (en) 1995-07-20
HUT72061A (en) 1996-03-28
ATE168379T1 (en) 1998-08-15
FI945596A0 (en) 1994-11-28
HK1013075A1 (en) 1999-08-13
DE69319732T2 (en) 1999-02-11
RU2126414C1 (en) 1999-02-20
IL105835A0 (en) 1993-09-22
NO944516L (en) 1995-01-27
MX9303243A (en) 1994-05-31
AU662991B2 (en) 1995-09-21
FI945596A (en) 1995-01-25
PH31246A (en) 1998-06-18
NZ253541A (en) 1997-01-29
DE69319732D1 (en) 1998-08-20

Similar Documents

Publication Publication Date Title
CN1039327C (en) Novel thio-substituted, nitrogen-containing, heterocyclic phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism
CN1042031C (en) Novel quaternary nitrogen-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism and methods of treating and preventing dental
CN1030253C (en) Methylenebisphosphonic acid derivatives
CN1699383A (en) Novel aryl fructose-1,6-bisphosphatase inhibitors
CN1030609C (en) Methylenebisphosphonic acid derivatives
CN1061049C (en) Sulfur-containing phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism
CN1289248A (en) Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases
CN1044912C (en) Novel thio-substituted cyclic phosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
JPH02279689A (en) N-substituted aminoalkanediphosphonic acid, its production and remedy containing it
CN1043424C (en) Novel quaternary nitrogen containing phosphonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
CN1255501A (en) Novel phosphonyl sulfonic ester compound and its medicinal compsns.
CN1048017C (en) Novel phosphonocarboxylate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism
TW318852B (en)
CN1085906A (en) The novel phosphonic acids compounds that contains quaternary nitrogen atoms, pharmaceutical composition and the method for the treatment of unusual calcium and phosphate metabolism
CN1134657A (en) Herbicidal AZA bisphosphonic acid compositions
CN1224018A (en) Phosphonic carboxylate compounds, pharmaceutical compositions contg. same

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C19 Lapse of patent right due to non-payment of the annual fee
CF01 Termination of patent right due to non-payment of annual fee